Multi-Compound and Drug-Combination Pharmacokinetic Research On Chinese Herbal Medicines

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REVIEW ARTICLE
Multi-compound and drug-combination pharmacokinetic
research on Chinese herbal medicines
Chuan Li1, Wei-wei Jia1, Jun-ling Yang1, Chen Cheng1 and Olajide E. Olaleye1
Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal
medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very
complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic
action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study
has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to
identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal
medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical
use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent
worldwide, even though it remains very controversial. Natural product–drug interactions have raised wide concerns about reduced
drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based
therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination
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pharmacokinetic approach was established to assess drug–drug interaction potential of herbal medicines and degree of
pharmacokinetic compatibility for multi-herb combination and herbal medicine–synthetic drug combination therapies. In this
review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination
pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic
research.
Keywords: Chinese herbal medicine; pharmacokinetics; multi-compound pharmacokinetic research; drug-combination

pharmacokinetic research; pharmacokinetic compatibility
Acta Pharmacologica Sinica (2022) 43:3080–3095; https://doi.org/10.1038/s41401-022-00983-7
INTRODUCTION marketing [7]. Historically, herbal medicines were not extensively

Chinese traditional medicine has provided for millennia a basis for tested before they were approved in China, owing to paucity of
disease treatment and health care to the Chinese nation and for the requisite technology at the time. Recently, a number of patent
China’s social stability. Particularly, this system of medicine has herbal medicines, extensively used in clinics, have shown
played a key role in management of various life-threatening therapeutic benefits in rigorous clinical trials, similar to those for
epidemics in China [1] and is officially recommended for COVID-19 synthetic drugs [8–12]. In addition, data from research on
[2–4]. Since the foundation of the People’s Republic of China in chemistry, pharmacodynamics, pharmacokinetics, drug–drug
1949, the Chinese government has attached much significance to interaction potential, real-world adverse reactions, and so on
the practice and growth of Chinese traditional medicine, with have become increasingly available [13–25]; this facilitates better
herbal medicines being regulated as drug products. Chinese defining the therapeutic benefits of herbal medicines and
herbal medicines are often formulated as tablet, capsule, and conditions for their safe use. All these research efforts are to
droplet pill for oral administration and as injectable formulation bring Chinese traditional medicine from empirical medicine into
for parenteral administration; they are required to be manufac- evidence-based one and are necessary to meet expanding
tured in compliance with good manufacturing practice as for regulatory requirements for Chinese herbal medicines and to
drugs by licensed pharmaceutical companies [5]. Many Chinese ensure their sustainable use.
herbal medicines are extensively used and prescribed by Unlike synthetic medicines, Chinese herbal medicines, which
physicians of Western medicine, as well as physicians of traditional are prepared from single medicinal herbs or much more
medicine. Since 1996, an ambitious plan has been underway in commonly from herb combinations, possess very complex
China to develop herbal medicines in line with contemporary chemical composition. Thus, identifying the chemical constituents
standards of pharmaceutical sciences [6]; the Chinese National that are together responsible for the therapeutic action of a
Medical Products Administration (NMPA) requires herbal medi- medicine is vital to provide support for clinical decision-making
cines to be proved safe, effective, and quality-consistent before related to the medicine’s therapeutic use. However, how to select
1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence: Chuan Li ([email protected])
Received: 5 August 2022 Accepted: 12 August 2022

Published online: 16 September 2022
© The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022
Pharmacokinetics: Chinese herbal medicines
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compounds from a complex herbal medicine for pharmacody- the dosed medicine [21–23, 26, 27, 38–47]. Notable difference
namic study remains a big hurdle in such identification efforts. To between the number of constituents present in the herbal
address this issue, we seek to identify potentially important medicine and that of compounds circulating after dosing the
compounds (bioavailable at the action loci with significant medicine is usually due to: (1) levels of the herbal constituents in
associated exposure levels after dosing an herbal medicine) and the medicine differing greatly (up to four or five orders of
to characterize their pharmacokinetics and disposition [26, 27]. We magnitude), (2) influences of the enterohepatic barrier, (3) tissue
refer to this as multi-compound pharmacokinetic research. Over distribution and systemic elimination (via biotransformation and
the past decade, great advances have been achieved in excretion into bile and urine), etc. Such a pharmacokinetic
methodology, associated techniques, and applications of such investigation needs to assess all the chemical constituents
multi-compound pharmacokinetic research on complex Chinese (particularly those with a compound dose >0.01 μmol/day)
herbal medicines [28–30]. present in the test herbal medicine with respect to body exposure
Another feature of Chinese herbal medicines is their typical use to them and can serve as a sieve to determine which herbal
in a multi-substance-acting manner; this is a polypharmacological compounds merit pharmacodynamic assessment [27]. In addition
approach that impacts multiple targets simultaneously for treating to identifying constituents that are together responsible for the
multifactorial diseases. The multi-substance-acting herbal therapy therapeutic action of a herbal medicine, the multi-compound
involves three levels, i.e., an herb’s multiple bioactive compounds pharmacokinetic investigation can also help identify constituents
acting in concert, multi-herb combination as a single medicine that are together responsible for the medicine’s adverse effect and
(‘FangjiPeiwu’ in Chinese), and coadministration of herbal that can together perpetrate pharmacokinetic DDIs with herbal
medicine and synthetic drug as separate medicines. Although medicines.
combination therapy represents a relatively simple way to gain Based on the preceding hypothesis, we recently investigated
polypharmacology, a high degree of pharmacokinetic compat- XueBiJing (an intravenous five-herb injection for sepsis care)
ibility (PKC) is needed among the co-administered drugs to ensure pharmacokinetics and pharmacodynamics and successfully iden-
the optimal therapeutic benefit. PKC is defined as absence of tified six constituents that could be together responsible for the
unintentional pharmacokinetic drug–drug interactions (DDIs) that injection’s anti-sepsis action (the details pending publication
can lead to reduced drug efficacy or increased drug toxicity elsewhere). After obtaining a comprehensive understanding of
[24, 29]. Concurrent use of complex natural products (including chemical composition of XueBiJing, multi-compound pharmaco-
herbal medicines) with conventional synthetic drugs is prevalent kinetic investigations were performed to identify potentially
worldwide but remains very controversial. Pharmacokinetic important XueBiJing compounds (i.e., those exhibiting significant
natural product–drug interactions have raised wide concerns levels of systemic exposure in humans and in cecal ligation and
about reduced drug efficacy or drug-related toxicity [31–33]. puncture/CLP rats, both intravenously receiving the injection) and
However, growing evidence shows that incorporating Chinese to characterize their pharmacokinetics and disposition. A total of
herbal medicines into synthetic medicine-based therapies for 12 major circulating compounds (unchanged and metabolized)
many multifactorial diseases delivers therapeutic benefits were identified from 124 constituents (compound dose,
[9–12, 34, 35]. To address this issue, we seek to assess DDI ≥0.01 μmol/day) of XueBiJing across the five component herbs.
potential of an herbal medicine and degree of PKC for After being verified by NMR and LC/MS–MS, all prepared and
combination therapies that include herbal medicines [29]. We purified entities of the major circulating compounds were
refer to this as drug-combination pharmacokinetic research. Over assessed in vitro and in CLP rats for their anti-sepsis activities on
the past years, much effort has been made to gain insight into immune response, inflammation, and coagulation. Six active
how to evaluate herbal medicines acting as a perpetrator XueBiJing compounds were identified and their different combi-
(involving multiple active compounds) or a victim in DDIs and nations were assessed by comparing with XueBiJing in CLP rats for
how to evaluate PKC degrees of therapeutic combinations of the primary therapeutic outcome percentage survival. Finally,
herbal medicine with synthetic medicine, reflecting clinical reality intravenously dosing a combination of the six compounds (at the
[24, 36–39]. In this Review, we describe the methodology, same respective compound doses as in XueBiJing) resulted in a
requirements, and applications of both multi-compound and percentage survival of CLP rats same as that by intravenously
drug-combination pharmacokinetic research on Chinese herbal dosing XueBiJing, and this was supported by bioequivalence of
medicines and discuss their future development. the six compounds between the combination and XueBiJing and
high degree of PKC for both the combination and XueBiJing (i.e.,
limited potential for interactions among the six active compounds
MULTI-COMPOUND PHARMACOKINETIC RESEARCH ON or for influences of other major circulating XueBiJing compounds
CHINESE HERBAL MEDICINES on these compounds).
Constituents responsible for therapeutic action of an herbal
medicine Requirements for multi-compound pharmacokinetic research on
For a complex Chinese herbal medicine, it is hypothesized that Chinese herbal medicines
only a few key constituents with favorable drug-like properties, Multi-compound pharmacokinetic investigation is a crucial step in
rather than all constituents present, are responsible for the identification of constituents that are together responsible for
medicine’s therapeutic action [26]. An herbal constituent can be therapeutic action of an herbal medicine, and the medicine to be
defined as ‘drug-like’ if it possesses the desired pharmacodynamic investigated needs to be an effective therapy in clinics. To this
potency, a wide safety margin, appropriate pharmacokinetic end, we proposed criteria for appropriately defining clinical
properties, an adequate compound dose from the dosed efficacy of a patent herbal medicine [15]. An herbal medicine
medicine, and compatibility with co-administered drugs. To fully can be considered ‘effective’ if it has clear therapeutic action, i.e.,
understand how a complex herbal medicine acts on the body to being intended for use in treatment, prevention, mitigation, cure,
deliver therapeutic benefits, the pharmacodynamic investigation or diagnosis of a specific disease. Clinical efficacy of the
should be properly integrated with the pharmacokinetic investi- therapeutic action should be demonstrated by well-designed
gation; this facilitates translation of the pharmacological findings and effectively executed clinical trials, meta-analysis of multiple
into clinical application. Multi-compound pharmacokinetic inves- similarly designed trials, and/or recommendations by authoritative
tigations of Chinese herbal medicines have indicated that human guidelines and expert consensuses. Based on understanding of
subjects and laboratory animals are significantly exposed to only a pathophysiology of the disease, such efficacy needs to be
few constituents, in their unchanged and/or metabolized forms, of supported by physiological and biochemical effects of the
Acta Pharmacologica Sinica (2022) 43:3080 – 3095

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medicine and/or its compounds, observed in clinical and/or defined as a significant discrepancy in an exposure parameter
animal studies, relevant to the therapeutic action. In addition, the (such as AUC, Cmax, or t1/2) or a primary pharmacokinetic
test medicine needs to be standardized for content of constitu- parameter (such as CLtot,p or Vd) of an herbal compound, between
ents and assessed for quality variability. The medicine should be of dosing the medicine and dosing the single compound at the same
high-quality consistency. dose level (for AUC and Cmax only) via the same administration
To identify chemical constituents that are together responsible route. Such pharmacokinetic matrix effects often result from
for the therapeutic action of an herbal medicine, the multi- substantial biotransformation of some other major constituents
compound pharmacokinetic investigation is performed and herbal (i.e., matrix compounds) in the medicine into the measured
compounds that merit pharmacodynamic assessment are deter- compound and/or from perpetration of a significant pharmaco-
mined. Bioavailability is the measure for this determination. Such kinetic interaction by the medicine’s matrix compounds with the
bioavailability is defined with respect to a certain type or certain measured compound. For example, circulating ginsenoside Rd
types of body exposure, which should be determined by the after intravenously dosing XueShuanTong (a lyophilized extract of
medicine’s therapeutic action and associated effects of the Panax notoginseng roots/Sanqi for intravenous administration) in
medicine and its compounds. For example, extracts of Ginkgo humans exhibited notably longer t1/2 (58‒307 h) than that after
biloba leaves are widely used for prevention and treatment of intravenous dosing of pure ginsenoside Rd (about 18 h), while
ischemic cardiovascular and cerebrovascular diseases and cerebral such t1/2 discrepancy in rats was 58 h versus 7.5 h [27, 39, 46, 68].
insufficiency. Clinical and experimental studies suggest that G. In this case, the matrix effect results from a transformation of
biloba leaf extracts could dilate arteries, improve coronary and ginsenoside Rb1 into ginsenoside Rd by hepatic glucosidase.
cerebral blood flow, protect endothelia, reduce lipid accumulation
in foam cells, decrease blood viscosity and viscoelasticity, Methodology for multi-compound pharmacokinetic research on
reduce erythrocyte malondialdehyde level, promote erythrocyte patent herbal medicines
deformability, etc [48–55]. Meanwhile, neuroprotective effects of Since most herbal medicines were, historically, not extensively
G. biloba leaf extracts have been documented, including tested before being approved (owing to paucity of the requisite
antioxidation, inhibition of amyloid-β aggregation, attenuation technology at the time), the multi-compound pharmacokinetic
of mitochondrion-induced apoptosis, normalization of neurogen- research is performed, particularly for those medicines effective
esis reduction in hippocampus, etc [56–59]. Flavonols and terpene and extensively used in clinics, to support their sustainable use as
lactones are two classes of bioactive constituents putatively medicines. For such patent medicines, methodology for multi-
responsible for the preceding effects of G. biloba leaf extracts compound pharmacokinetic research is an integration of multiple
[60–62]. To understand bioavailability of these ginkgo compounds studies and methods, i.e., comprising one forerunner study, one
after dosing the extract, multi-compound pharmacokinetic main study, two types of supportive studies, and three groups of
research was focused on systemic and cerebral exposure to the supportive techniques (Fig. 1).
compounds [40, 41, 45]. To date, the human commensal intestinal The forerunner study is composition analysis of the test herbal
microbiota has increasingly gained interest for its important roles medicine; this is pivotal for ensuring the whole multi-compound
in training of host immunity, digesting food, regulating gut pharmacokinetic investigation to be ‘precision without omission’.
endocrine function and neurological signaling, modifying drug Such composition analysis is usually based on liquid
action and metabolism, eliminating toxins, and producing chromatography–mass spectrometry for polar and nonvolatile
numerous compounds that influence the host [63, 64]. Imbalances compounds and gas chromatography–mass spectrometry for
in the composition and function of the microbiota are associated nonpolar and volatile compounds and involves detection,
with diseases ranging from localized gastroenterologic disorders characterization, and quantification of the medicine’s constituents.
to neurologic, respiratory, metabolic, hepatic, cardiovascular The assay for composition analysis is required to be of high
diseases, etc. The microbiota is a major player in human health ‘analyte-capacity’ simultaneously for the three component steps:
and disease and there has been considerable interest in sample preparation, chromatographic separation, and mass
therapeutic targeting the microbiota as well as mining this rich spectrometric detection. The levels of detected constituents of
source in drug discovery efforts [65–67]. To better understand the medicine are defined with respect to compound dose from
interactions between herbal medicines and the intestinal micro- the dosed medicine; the dose is estimated by multiplying the
biota, the multi-compound pharmacokinetic research also content level of the constituent by the dose of the medicine.
involves investigating access of the medicines’ compounds to Although both the compound dose and the content level are
the intestinal microbiota by determining intestine-luminal expo- equally governing factors in generating systemic exposure to the
sure to the compounds. constituents, unchanged and metabolized, after dosing medicine,
Successful identification of constituents that are together the former, rather than the latter, can be used to compare
responsible for the therapeutic action of an herbal medicine different medicines for the compound. The assay is also used to
necessitates a comprehensive approach to the multi-compound evaluate quality variability of the medicine, particularly for those
pharmacokinetic investigation such that the potentially important constituents with a compound dose ≥1 μmol/day, because only
herbal compounds are singled out with their accurate pharmaco- one batch of medicine is usually assessed in the pharmacokinetic
kinetic and disposition data and that no such compound is missed investigation. High quality consistency among different batches of
(in a few words, ‘precision without omission’). To this end, the medicine suggests the pharmacokinetic data of one test batch is
multi-compound pharmacokinetic research should be performed applicable to other batches.
on the basis of a comprehensive understanding of the chemical The main study is a human pharmacokinetic study by dosing
composition of the test medicine. To deal with the complex the test herbal medicine. Constituents, bioavailable in unchanged
chemical composition of herbal medicines, the pharmacokinetic and/or metabolized forms with significant levels of body exposure,
research is performed by integrating human study with various are identified in the human study where the volunteers receive
animal and in vitro studies and by integrating experimental the medicine usually at the label daily dose. Such identification
approaches with informatics-based approach. In addition, phar- should be achieved for each component herb of the medicine (to
macokinetic matrix effects of an herbal medicine on pharmaco- reflect the entirety of the medicine’s formula), because all the
kinetics of its major circulating compounds should be assessed in component herbs are believed to contribute to the therapeutic
humans but more frequently in experimental animals (because action of the medicine. In a human pharmacokinetic study, three
single compound formulation that can be dosed is frequently not types of samples, i.e., blood, urine, and feces, are usually collected
available for humans). The pharmacokinetic matrix effect is before and after the volunteers receive a single dose and

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Fig. 1 An overview of approach to multi-compound pharmacokinetic research on Chinese herbal medicines. (Reprinted from Li et al., 2021
[30] with permission of Acta Pharm Sin).
sometimes repeated doses of the medicine. Blood samples are those herbal compounds without significant interspecies differ-
frequently heparinized and centrifuged to yield the respective ences. Frequently performed supportive animal studies include:
plasma samples, which are analyzed to assess systemic exposure studies by dosing individual chemical constituents (such as for
to unchanged and/or metabolized constituents after dosing and assessing pharmacokinetic matrix effects of the test medicine) and
pharmacokinetics of the major circulating compounds. Urine by dosing via intravenous administration route and studies of
samples are analyzed to facilitate assessing the systemic exposure dose–exposure correlation, tissue distribution, brain microdialysis,
to herbal constituents and to assess the role of renal excretion in hepatobiliary excretion, enterohepatic circulation, portal-vein
elimination of the major circulating compounds and associated exposure, and intestine-luminal movement and disposition.
mechanisms. Feces samples are analyzed to assess intestine- Besides evaluating the preceding interspecies similarities and
luminal exposure to herbal constituents and their intestinal differences, the in vitro studies are performed to characterize
absorption, microbiota-mediated metabolism, and fecal excretion. important compounds of the medicine with respect to in vivo
Despite its significance to an herbal medicine, not all the desired phase I and II metabolism, transport, and their interplay. In
pharmacokinetic data of the constituents after dosing the addition, in vitro studies of herbal compounds also involve
medicine can be obtained from a human pharmacokinetic study. characterizing, under anaerobic conditions, intestinal microbiota-
Data for tissue distribution, hepatobiliary excretion, etc. are usually mediated metabolism and assessing membrane permeability,
difficult to be obtained from the human study. When intravenous water solubility, plasma protein binding, lysosomal trapping,
formulation of the medicine is not available for dosing in humans, blood-to-plasma ratio, etc.
the pharmacokinetic parameters oral bioavailability (F), plasma The three groups of supportive techniques in pharmacokinetic
total clearance (CLtot,p), apparent volume of distribution (Vd), etc. investigation of an herbal medicine are methods for literature
often can not be obtained in humans. Dosing individual mining, sample analysis, and data processing. The literature
constituent compound is often another challenge faced in the mining is performed to improve the efficiency and performance of
human pharmacokinetic study. To address this issue, the human the preceding experimental studies for dealing with a complex
study is often supplemented with various animal and in vitro herbal medicine. Literature mining (comprising retrieval, extrac-
studies. tion, and review of information) involves defining desired
The two types of supportive studies are performed in information, setting right search terms, and using appropriate
experimental animals and in vitro. Regarding the animal studies electronic databases to meet the aim of the whole pharmacoki-
that are performed to gain additional pharmacokinetic informa- netic investigation and the needs of each component experi-
tion on important constituents of an herbal medicine, it is pivotal mental study. Regarding the sample analysis, four types of
to evaluate interspecies similarities and differences between analytical methods are frequently developed and used in the
animals (such as rats) and humans in body exposure, enzyme- pharmacokinetic investigation, i.e., assays for composition analysis
mediated metabolism, transporter-mediated transport, plasma of the herbal medicine, for chemical profiling of herbal
protein binding, etc. To compare body exposure to constituents compounds (unchanged and metabolized) in various in vivo study
between animals and humans, blood, urine, and feces samples are samples, for quantification of selected herbal compounds in
collected from the animals receiving the medicine and analyzed various in vivo and in vitro study samples, and for quantification of
for the unchanged and metabolized constituents. The data on tool compounds (such as known metabolites and known
animal exposure to the constituents are compared with the substrates for positive control) in various in vitro study samples.
respective human data gained from the preceding main study. To The first two types of assay are needed to be of high analyte-
compare constituents’ enzyme-mediated metabolism, transporter- capacity, while the last two types are needed to be of high
mediated transport, and plasma protein binding between animals sample-throughput. Precisely and comprehensively obtaining the
and humans, in vitro studies of the compounds with animal desired information is the core of sample analysis in a
proteins are performed in parallel with the respective in vitro pharmacokinetic investigation. To achieve successful analysis, five
studies with human proteins. Based on these comparisons, elements should be carefully considered, i.e., information mining
supportive animal pharmacokinetic studies are performed for before assay development, collection of right samples, analyte

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prediction or selection of right analytes, analytical technique and notoginsenoside R1 of 20(S)-protopanaxatriol-type (ppt-type;
development and condition optimization, and data processing. with a free hydroxyl group at the C-3 and O-attached sugar
This manner of sample analysis is referred to as ‘one core and five moieties at C6 and/or C20 positions), are the major bioactive
elements’. The data processing in a pharmacokinetic investigation constituents of Sanqi. Despite their structural similarity, signifi-
of an herbal medicine frequently involves using literature-mined cantly different elimination kinetics occurs between the ppd-type
data to build or update herb-constituent libraries that support and ppt-type ginsenosides, as indicated by human t1/2 of 53.5‒
composition analysis of the herbal medicine, using measured 175.9 h for the former and 1.3‒1.4 h for the later [39]. The different
compound doses to rank constituents detected in the medicine elimination kinetics results from differences both in hepatobiliary
with respect to compound dose, using literature-mined data or excretion and in renal excretion [36]. Unlike the ppt-type
metabolism software to predict metabolism of the medicine’s ginsenosides, the human hepatic transporters OATP1B3 and
major constituents, using measured levels of body exposure to MRP2/BCRP/BSEP/MDR-1 do not mediate the excretion of ppd-
rank bioavailable constituents (unchanged and metabolized) in type ginsenosides. In addition, extensive plasma protein binding
humans or animals receiving the medicine, proposing metabolic limits glomerular-filtration-based excretion of the ppd-type
pathways of major constituents, using pharmacokinetics software ginsenosides, while low plasma protein binding facilitates such
to estimate pharmacokinetic parameters of the medicine’s major renal excretion of the ppt-type ginsenosides.
circulating compounds, using physiologically based pharmacoki- Significant interspecies differences in body exposure, pharma-
netic (PBPK) modeling software to predict pharmacokinetics and cokinetics, and interactions with drug metabolizing enzymes and
disposition of the major circulating compounds, using GraFit transporters are another factors that need to be considered in
software or the like to estimate metabolism and transport kinetic multi-compound pharmacokinetic research on herbal medicines.
parameters of the medicine’s important compounds, using For example, senkyunolides G and I are two phthalide constituents
statistics software to perform statistical analysis, etc. of XueBiJing injection and originate from the injection’s compo-
nent herbs Ligusticum chuanxiong rhizomes (Chuanxiong) and
Differential pharmacokinetics of a class of herbal compounds and Angelica sinensis roots (Danggui). After intravenously dosing
interspecies differences XueBiJing, both the phthalides are major circulating compounds
Different classes of constituents may have significantly different in humans, but only senkyunolide I is the major circulating
compound doses from a dosed herbal medicine. In this case, the phthalide in rats with senkyunolide G limitedly detected [23].
levels of systemic exposure to constituents of different classes can Terpene lactones are a class of bioactive constituents of
be very different. Even for a class of constituents with comparable ShuXueNing injection (a botanical drug product of Ginkgo biloba
compound dose levels, the compounds can also exhibit sig- leaf extract, used as add-on therapies in patients with ischemic
nificantly different body exposure, pharmacokinetics, and interac- cardiovascular and cerebrovascular diseases). In humans, the
tions with drug metabolizing enzymes and transporters. For terpene lactones ginkgolides A (molecular mass, 408 Da) and B
example, phenolic constituents of Salvia miltiorrhiza roots (424 Da) were eliminated from the systemic circulation predomi-
(Danshen) are caffeic acid derivatives, occurring as monomers nantly via glomerular-filtration-based renal excretion [45]. How-
(tanshinol), dimers (rosmarinic acid and salvianolic acid D), trimers ever, these two terpene lactones were eliminated both via renal
(salvianolic acid A and lithospermic acid), and tetramers (salvia- and hepatobiliary excretion in rats [41]. After orally dosing Sanqi
nolic acid B), these Danshen compounds contain one or more extract in humans, ppt-type ginsenosides are extensively degly-
catechol moieties with one or more carboxyl groups. In addition, cosylated by the colonic microbiota into 20(S)-protopanaxatriol,
protocatechuic aldehyde is also a major Danshen constituent, which can be absorbed in the colon and oxidized into several
which contains a catechol compound without any carboxyl group. circulating metabolites by the host enterohepatic CYP3A. [42]
After oral administration of compound Danshen droplet pills However, such microbial deglycosylation occurs poorly in rats [27].
(a Danshen-containing herbal medicine extensively used to treat
angina pectoris) in humans, tanshinol was the only Danshen Research example: pharmacokinetics-based identification of
constituent that exhibited significant systemic exposure [26]. The pseudoaldosterogenic compounds of Glycyrrhiza uralensis roots
other Danshen constituents salvianolic acids A, B, and D, (Gancao)
rosmarinic acid, lithospermic acid, and protocatechuic aldehyde Glycyrrhiza uralensis root (Gancao) is a widely used medicinal herb
were either poorly absorbed from the gastrointestinal tract or in Chinese traditional medicine. However, Gancao-induced pseu-
were extensively metabolized, which resulted in poor detection of doaldosteronism (characterized by hypokalaemia, hypertension,
their unchanged forms in plasma after dosing. After intravenously and peripheral edema) could be an adverse effect of Gancao-
dosing DanHong injection (another Danshen-containing herbal containing medicines and dietary products, via inhibition of renal
medicine extensively used to treat coronary artery disease and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) [70]. Given
ischemic stroke), these Danshen phenolic compounds exhibit that Gancao is widely used as a component in Chinese herbal
different interactions with hepatic and renal uptake transporters, medicines, uncovering the compounds that are together respon-
resulting in different profiles of hepatobiliary and renal excretion sible for the Gancao-induced adverse effect has implications for
[43, 69]. Lithospermic acid and salvianolic acid B (both >500 Da) precisely defining conditions for safe use of Gancao-containing
underwent systemic elimination, initiated by OATP1B1/OATP1B3- medicines, such as LianhuaQingwen capsule (an herbal medicine
mediated hepatic uptake; rosmarinic acid and salvianolic acid D officially recommended as treatment for COVID-19 in China).
(350–450 Da), initiated by OATP1B1/OATP1B3/OAT2-mediated Although glycyrrhizin is a major Gancao constituent with
hepatic uptake and by OAT1/2-mediated renal uptake; and bioactivities such as inhibiting the replication of the SARS-
protocatechuic acid and tanshinol (both <200 Da), initiated by associated virus, [71] this saponin and its several metabolites
OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic have been documented to inhibit 11β-HSD2 [72–80]. We
uptake. Here, protocatechuic acid is an oxidized metabolite of identified pseudoaldosterogenic Gancao compounds from circu-
protocatechuic aldehyde by hepatic aldehyde dehydrogenase. lating Gancao compounds of dosed LianhuaQingwen, based on
Panax notoginseng roots (Sanqi) is a Chinese medicinal herb the compounds’ in vivo access to and in vitro inhibition of human
extensively used to treat ischemic cardiovascular and cerebrovas- renal 11β-HSD2 [47]. This renal enzyme is highly expressed in
cular diseases. Triterpene saponins (most of them derived from the epithelia of the distal tubule and collecting duct [81, 82].
tetracyclic dammarane), including ginsenoside Rb1 and ginseno- After composition analysis of LianhuaQingwen for constituents
side Rd of 20(S)-protopanaxadiol-type (ppd-type; with O-attached originating from Gancao, we performed a multi-compound
sugar moieties at C3 and/or C20 positions) and ginsenoside Rg1 pharmacokinetic investigation by dosing the capsule in human

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Fig. 2 A schematic overview of pharmacokinetics-based identification of the pseudoaldosterogenic compounds glycyrrhetic acid (8) and
24-hydroxyglycyrrhetic acid (M2D). The Gancao constituents glycyrrhizin (1) and licorice saponin G2 (2) are metabolically activated by
glucuronidase of the colonic microbiota to the metabolites 8 and M2D, respectively, which can access (via passive tubular reabsorption) and
inhibit renal 11β-HSD2. (Reprinted from Lan et al., 2021 [47] with permission of Acta Pharmacol Sin).
volunteers, as well as in rats, to identify the major circulating withdrawn, and diuretics (such as spironolactone and eplerenone)
Gancao compounds and to assess their in vivo access to renal and drugs (that can alkalinize pH of tubular fluid) may be
11β-HSD2. The identified potentially important Gancao com- administered to reduce tubular reabsorption of 8 and M2D.
pounds were then assessed in vitro for their inhibition of human
renal 11β-HSD2. Among the 41 Gancao constituents detected in
LianhuaQingwen, glycyrrhizin (1) and licorice saponin G2 (2) are DRUG-COMBINATION PHARMACOKINETIC RESEARCH ON
the major Gancao saponin constituents. Poor intestinal absorption CHINESE HERBAL MEDICINES
of 1 and 2 and their access to colonic microbiota result in Pharmacokinetic compatibility (PKC) of a combination therapy
significant levels of their respective deglycosylated metabolites In the practice of Chinese traditional medicine, multi-herb
glycyrrhetic acid (8) and 24-hydroxyglycyrrhetic acid (M2D) combination therapies (FangjiPeiwu) have been extensively used
occurring in the systemic circulation after colonic absorption. to achieve therapeutic advantages of enhanced efficacy and
These circulating metabolites are glucuronized/sulfated in the liver safety. Two principles, i.e., QiqingHehe and JunChenZuoShi, guide
and then excreted into bile. Hepatic oxidation of 8 yields M2D. how to select and combine herbs for the multi-herb combination
Due to their good membrane permeability, circulating 8 and M2D therapy [83]. QiqingHehe sums up seven ways of using herbs, i.e.,
gain access to (via glomerular filtration and then passive tubular using an herb alone (Danxing) and using herbs in combination (to
reabsorption) and potently inhibit renal 11β-HSD2. Collectively, 1 achieve beneficial combination effects and to avoid adverse
and 2 are metabolically activated to the pseudoaldosterogenic combination effects). The beneficial combination effects are
compounds 8 and M2D (Fig. 2). Although the microbial Xiangxu (the salutary effects of two herbs of similar actions being
metabolites 8 and M2D are not the only Gancao-related synergistic), Xiangshi (the salutary effect of an herb being
compounds exhibiting inhibitory activities on 11β-HSD2, they enhanced by another herb exerting an additional or different
are the only ones that are bioaccessible for the renal enzyme. Both action), Xiangwei (the adverse effect of an herb being reduced or
8 and M2D are extensively bound to plasma albumin (fu, <1%), minimized by another herb), and Xiangsha (an herb reducing or
limiting the renal glomerular filtration of 8 and M2D, with such minimizing the adverse effect of another herb), while the adverse
binding acting as a ‘safety belt’ that allows the herb Gancao and combination effects are Xiang’e (the salutary effect of an herb
Gancao-containing medicines to be widely used in Chinese being reduced when combined with another herb) and Xiangfan
traditional medicine. This finding allows us watch out for people (an herb producing adverse effect when combined with another
who may susceptible to Gancao-induced pseudoaldosteronism, herb). The QiqingHehe principle tells that combining herbs are not
i.e., patients with hypoalbuminemia. only necessarily beneficial/desirable but may also lead to
Excessive and prolonged use of Gancao-containing herbal undesirable/harmful effects and that the component herbs of
medicines and dietary products, as well as glycyrrhizin formula- such a combination should work in concert with one another to
tions, is a main cause of pseudoaldosteronism [72]. To ensure safe achieve desired therapeutic outcome. For multi-herb combination
use of Gancao-containing medicines like LianhuaQingwen, (1) it is therapies, pharmacokinetic interactions among the component
pivotal to increase awareness of Gancao-induced pseudoaldoster- herbs remain a major concern. To this end, a combination therapy
onism; (2) caution should be exercised when a Gancao-containing necessitates evaluation for PKC among its herbs. Recent advances
medicine is administered concurrently with other Gancao- in multi-compound pharmacokinetic research on Chinese herbal
containing medicines and dietary products; (3) a Gancao- medicines are now revolutionizing the analytical toolbox available
containing medicine should not be administered to patients with to support evaluation and understanding of herb-herb interaction
decreased 11β-HSD2 activity, hypokalemia, hypertension, potentials in a multi-herb combination, as well as PKC degree of
impaired liver function, or hypoalbuminemia; and (4) once the multi-herb combination. The JunChenZuoShi principle calls for
pseudoaldosteronism occurs, the Gancao-containing medicine hierarchy in a Chinese multi-herb combination by ranking the
and co-administered Gancao-containing products should be component herbs in order of importance of their therapeutic role

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in the combination. Component herbs of such a combination herbal medicines are regarded as therapeutic, hence are regulated
serve differently as monarch (the chief herb(s) treating the as drug products in China. Therefore, when a Chinese herbal
disease), minister (the herb(s) strengthening the therapeutic medicine is used concurrently with synthetic medicines, the
action of the monarch herb by acting similarly), adjuvant (the herbal medicine can act as not only the perpetrator but also the
herb(s) treating the secondary comorbidity, reducing adverse victim in potential DDIs. Investigation of potentials both for herbal
effects of the monarch and minister herbs, or counteracting the medicine–synthetic drug interactions and synthetic drug–herbal
drastic action of the monarch herb to suit the patient), and medicine interactions is important to facilitate evaluation of PKC
guiding herbs (the herb(s) facilitating the other component herbs’ degrees of a Chinese herbal medicine and the concomitant
access to their sites of action or agreeing in a friendly way). For a synthetic drug. High degree of pharmacokinetic compatibility
multi-herb combination, the role of a component herb is (PKC) is desired for success of such combination therapy.
associated with the active compounds that it provides. The
importance of such compounds depends on their pharmacody- Chinese herbal medicine as potential perpetrator of
namic activities and pharmacokinetic profiles, particularly their pharmacokinetic DDI
exposure levels and associated target engagement in the body. Natural product–drug interactions are widely recognized as an
The traditional ‘one drug-one target’ paradigm is based on a issue for many drug therapies. However, the evidence of such
direct cause−effect relationship between the activity of a gene interactions is often based on data derived from in vitro or animal
product and a particular phenotype. Consequently, a ‘magic studies, isolated case reports that frequently lack pertinent
bullet’ drug, which is designed to act on a single target with high information, or some clinical trial results. Early evaluations of
selectivity and potency, is considered able to remedy a potential natural product–drug interactions were fraught with
pathological phenotype, with limited adverse reactions. Although difficulties and often yielded inconclusive and contradictory
the idea of the ‘magic bullet’ is great, it is probably not the answer results. These DDI investigations of natural products did not
to treating multifactorial diseases [84, 85]. Indeed, there has been reveal their compounds that could together perpetrate the
wide recognition that many multifactorial diseases with unmet potential DDIs or define the conditions under which the
therapeutic needs may require the polypharmacological approach interactions could take place. Also, the natural products tested
to modulating multiple targets in concert. Polypharmacology were not systematically characterized for their chemical composi-
encompasses both the combination therapy with multiple drugs tion and pharmacokinetics in humans. In other words, a multi-
acting on different targets and the multi-target single drug compound pharmacokinetic investigation was not performed to
[86–88]. Although multi-target drugs have experienced growing facilitate drug-combination pharmacokinetic investigation of the
interest [89–91], combination therapies are among the most herbal medicine by singling out their compounds that were
promising and simple avenues towards treating multifactorial bioavailable with significant body exposure levels and accessible
diseases [92–94]. Combination therapies are used to therapeutic to the human interacting protein (drug metabolizing enzyme or
advantage, because the beneficial effects are synergistic or drug transporter). Thus, more rigorous drug-combination pharma-
additive by acting on different targets, because beneficial effects cokinetic research is needed.
can be achieved with fewer adverse effects by using submaximal When documented case reports suggest possible DDIs are per-
drug doses, or because drug resistance can be overcome. The petrated by an herbal medicine or when chemical constituents of
combination therapy has proven effective in combating several an herbal medicine show significant modulation of drug
multifactorial diseases, including acquired immune deficiency metabolizing enzymes and/or drug transporters, the herbal
syndrome, hypertension, and cancer [95–97]. Despite these medicine should be considered for evaluation of its potential for
advantages, DDI issue is a major concern in the development of perpetrating DDI. Unlike synthetic drugs that usually contain
combination therapies. DDIs can occur at all levels, particularly single chemical entities, herbal medicines often contain multiple
pharmacokinetic DDIs that can lead to variability in drug exposure constituents, many of them bearing structural resemblance. Such
and disposition. Failure to identify the DDI risk can be a major structurally related herbal compounds can interact with the same
source of overdosing or undertreatment, with severe clinical interacting protein to different extents and together perpetrate
consequences. Accordingly, evaluating PKC degree is necessary to the DDI. Accurate evaluation of interaction potential of an herbal
understand whether the therapeutic advantage of combination medicine relies on identifying all its constituents that may
therapy is obstructed by serious pharmacokinetic DDIs. contribute considerably to perpetrating the DDI. Recently, we
In China, treatment of diseases using Chinese traditional have proposed an approach for rigorously investigating potential
medicine combined with Western medicine is a common practice. of an herbal medicine for perpetrating DDI: (1) thoroughly
Many herbal medicines are incorporated into synthetic drug- characterizing the chemical composition of the test herbal
based management of multifactorial diseases for therapeutic medicine; (2) identifying major circulating herbal compounds,
advantage, either because the salutary effects of the two types of unchanged and metabolized, that are accessible to the locus of
medicines are complementary and/or synergistic or because such interaction; (3) assessing the modulation potencies of these herbal
effects can be achieved with reduced drug adverse effects or compounds on the relevant interacting proteins; (4) characterizing
reduced drug resistance [9–12, 98, 99]. In USA and many European the herbal compounds’ disposition factors that can affect their
countries, the use of dietary supplements or herbal medicinal exposure levels and access to the interacting protein; and (5)
products is prevalent, particularly in patient populations already evaluating how the identified herbal compounds together
exposed to synthetic medicines. Natural products, either as herbal modulate the same interacting protein [38]. Results from such
medicines or as dietary supplements, can perpetrate clinically investigations will inform PBPK model-based prediction and, if
significant DDIs, leading to undesired alterations in exposure and necessary, clinical DDI studies of the herbal medicine.
disposition of the concomitant drugs [31, 33, 100]. For example, The triterpene saponins ginsenosides of ppd-type and ppt-type
both grapefruit juice and St. John’s wort can perpetrate clinically are the major bioactive constituents of three medicinal ginseng
significant natural product–drug interactions, by inhibiting and herbs Panax ginseng root (Renshen), P. notoginseng root (Sanqi),
inducing CYP3A4, respectively [101–106]. These textbook exam- and P. quinquefolius root (Xiyangshen). Considerable speculation
ples of natural product–drug interaction have raised wide regarding DDIs perpetrated by products of ginseng herb frequents
concerns about concurrent use of natural products and synthetic the literature, but conclusive evidence for such interactions is
drugs, suggesting some overlap in interactions with drug lacking [31, 32, 107–111]. For example, significantly reduced levels
metabolizing enzymes and/or drug transporters between the of systemic exposure to oral midazolam (a probe substrate
natural product and the synthetic drug. In addition, Chinese for CYP3A phenotyping) after a 28-day oral administration of

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P. ginseng capsule (500 mg, b.i.d.; Vitamer, CA, USA) in healthy ginsenosides selectively inhibit OATP1B3, XueShuanTong is likely
volunteers were reported, suggesting possible induction of CYP3A to alter pharmacokinetics of selective substrates of OATP1B3
by the botanical product [112]. However, another human DDI when co-administered, rather than selective substrates of
investigation reported that 28-day administration of the same OATP1B1 or dual substrates of OATP1B1/1B3. Several selective
P. ginseng capsule (500 mg, t.i.d.; Vitamer, CA, USA) did not OATP1B3 substrates, such as cholecystokinin-8, telmisartan,
significantly alter midazolam metabolism [113]. In addition to the amanitin, dioscin, convallatoxin, ouabain, dihydroouabain, ouaba-
approach of midazolam phenotyping being different between the genin, and ppt-type ginsenosides, have been reported
two investigations, information was not provided on interaction- [36, 114–118]. Information on potential DDIs should be an
related human pharmacokinetics of the test botanical products important part of the patient information leaflet of herbal
and the quality consistency between the product lots used in the medicines. However, most Chinese herbal medicines currently
two investigations. Ginsenosides are the main pharmacologically lack such information. Increased awareness of ginsenosides’
active constituents of XueShuanTong, a lyophilized extract of pharmacokinetics and XueShuanTong-drug interaction potential
Sanqi for intravenous administration. Recently, ginsenosides, will help ensure safe use and effective combination therapies of
particularly those of ppd-type, were found to potently inhibit XueShuanTong and synthetic drugs.
hepatic OATP1B3 and, to a lesser extent, OATP1B1 [36, 38]. Given
that co-medication of XueShuanTong with synthetic drugs is Chinese herbal medicine as potential victim of pharmacokinetic
common for treatment of ischemic cardiovascular or cerebrovas- DDI
cular diseases and that levels of systemic exposure to ginseno- In China, herbal medicines are regarded as therapeutic and
sides via intravenous administration route are much higher than regulated as drug products. This requires evaluating potential of
the respective ones via oral administration route [39, 42], DDI Chinese herbal medicines not only for perpetrating DDIs but also
information is essential for making clinical decision on therapies for acting as victim in DDIs. Natural products such as dietary
co-administering XueShuanTong with synthetic drugs. To this end, supplements in many Western countries are not drug products;
XueShuanTong-drug interaction potential was evaluated and the their therapeutic effects and adverse effects do not need to be
investigation focused on assessment of CYP3A induction and and are normally not well defined, like those of conventional
OATP1B inhibition. drugs. So, little is known which compounds are responsible for
Literature-mined information, as well as our earlier related study these effects of the natural products. Unlike natural product–drug
findings [39, 42], was used to facilitate the DDI investigation by interactions, drug-natural product interactions have been limitedly
avoiding missing potentially important XueShuanTong com- investigated and documented for their potential.
pounds. After thorough composition analysis of XueShuanTong As a prerequisite for evaluating drug–herbal medicine interac-
for ginsenosides and evaluation of associated lot-to-lot quality tion potential, it should be understood which compounds are
variability, a multi-compound pharmacokinetic study was per- responsible for therapeutic or adverse effect of the test herbal
formed in healthy volunteers (intravenously receiving XueShuan- medicine and whether altered levels of exposure to these active
Tong) to identify circulating ginsenosides, unchanged and compounds are associated with reduced efficacy or increased
metabolized, with significant levels of systemic exposure and toxicity of the herbal medicine. An herbal medicine is deemed a
their pharmacokinetics that was important for perpetrating the potential victim of DDI if the enzyme(s) or transporter(s) mediating
DDI. Two types of XueShuanTong-perpetrated DDI study were the intestinal absorption or systemic elimination of its active
performed: (1) evaluation of potential of XueShuanTong for compounds can be inhibited without other route(s) that can
inducing CYP3A in healthy volunteers and the results were significantly compensate the impaired route or if the interacting
confirmed by a cell-based induction study with respect to mRNA protein(s) can be induced.
level and enzyme activity, using the major circulating ginseno- Inflammation in the liver precedes and promotes the progres-
sides and (2) prediction of XueShuanTong’s potential for inhibiting sion towards liver cirrhosis and hepatocellular carcinoma. Intrave-
OATP1B3 by the major circulating ginsenosides using their time- nous glycyrrhizin has been incorporated into the management of
dependent unbound plasma concentrations in humans. In the liver diseases (including cause-specific treatment) due to its
CYP3A induction study, possible influence of enzyme inhibition on additional value of anti-inflammation and hepatoprotection
the results was assessed in vivo and in vitro. In the OATP1B [119–123]. Glycyrrhizin, triterpene saponin, is a major constituent
inhibition study, inhibition of OATP1B together by multiple present in Glycyrrhiza uralensis root (Gancao) and other medicinal
XueShuanTong ginsenosides was assessed in vitro, and the data Gancao species (G. inflate root and G. glabra root). Despite the
were processed using the Chou-Talalay method. Samples were therapeutic effects, high dose and prolonged use of intravenous
analyzed by liquid chromatography/mass spectrometry. glycyrrhizin formulations, as specified on the patient information
A total of 50 ginsenosides with compound doses of >0.01 μmol/ leaflets, possibly induce pseudoaldosteronism by inhibiting 11β-
day were detected and characterized in XueShuanTong: 14 ppd- HSD2. Pseudoaldosteronism can result from increased AUC0-∞ of
type ginsenosides, 18 ppt-type ginsenosides, and 18 ginsenosides glycyrrhizin. Unlike oral administration, intravenous administration
of other types. As shown in Fig. 3, ginsenosides Rb1 and Rd of yields unchanged glycyrrhizin as the major circulating form.
ppd-type and ginsenoside Rg1 and notoginsenoside R1 of ppt- Unchanged glycyrrhizin is eliminated mainly via hepatobiliary
type were the major circulating XueShuanTong compounds; their excretion, rather than renal excretion and metabolism. Therefore,
DDI-related pharmacokinetics comprised compound dose- level of systemic exposure to and hepatobiliary excretion of
dependent levels of systemic exposure and, for ginsenosides unchanged glycyrrhizin are factors influencing intravenous
Rb1 and Rd, long terminal half-lives (32‒57 and 58‒307 h, glycyrrhizin-induced pseudoaldosteronism. To this end, human
respectively) and low unbound fractions in plasma (0.8%‒2.9% transporters mediating hepatobiliary excretion of glycyrrhizin
and 0.4%‒3.0%, respectively). Repeatedly dosing intravenous were characterized at the cellular and vesicular levels and
XueShuanTong does not induce human CYP3A4/3A5. Based on compared with rat hepatic transporters. The role of Oatp1b2 in
human pharmacokinetics and overall inhibitory potency of glycyrrhizin’s elimination and pharmacokinetics was evaluated in
its bioavailable ginsenosides, intravenously dosed XueShuanTong rats using the inhibitor rifampin. A PBPK model for glycyrrhizin,
is found to have high potential for OATP1B3-mediated incorporating transporter-mediated hepatobiliary excretion, was
drug interactions, which is attributed chiefly to ginsenoside Rb1. established and applied to predict human systemic exposure to
This finding informs a need for further PBPK model-based glycyrrhizin and its potential as the victim in DDI [37].
prediction of the interaction potential for XueShuanTong and, if Glycyrrhizin is of poor membrane permeability. Hepatobiliary
necessary, clinical DDI studies of XueShuanTong. Because the excretion of glycyrrhizin involves human OATP1B1/1B3 (Oatp1b2

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Fig. 3 Chemical composition, circulating compounds, and DDI potential of XueShuanTong. Ginsenosides present in XueShuanTong (a),
their systemic exposure and renal excretion in human volunteers who received a 2.5-h infusion of XueShuanTong at 500 mg/person (b), and
estimated total DDI indexes on OATP1B1 and OATP1B3 for a single 2.5-h intravenous infusion of XueShuanTong at 500 mg/person and for
repeated doses of XueShuanTong at 500 mg/person every day on day 18 (c). Chemical structures of the major circulating ginsenosides after
dosing XueShuanTong are shown in panel (d). The XueshuanTong constituents 1‒14 are ppd-type ginsenosides; 31‒48 are ppt-type
ginsenosides; and 51‒68 are other type ginsenosides. M4, M6, M8, and M11‒M14 are metabolites of the ppt-type ginsenosides (see Ref. [42]
for more information about these metabolites). 1, ginsenoside Rb1; 2, ginsenoside Rd; 31, ginsenoside Rg1; 32, notoginsenoside R1; PPD, 20(S)-
protopanaxadiol; and PPT, 20(S)-protopanaxatriol. Glc glucopyranosyl, Xyl xylopyranosyl. (Reprinted from Pintusophon et al., 2019 [39] with
permission of Acta Pharmacol Sin).
in rats)-mediated hepatic uptake from blood and human MRP2/ acting antiviral agents paritaprevir and ritonavir) used in clinics
BCRP/BSEP/MDR1 (Mrp2/Bcrp/Bsep in rats)-mediated hepatic and that substantial impairment of OATP1B1/1B3 activities (by
efflux into bile. No other hepatic transporters exhibit such ≥80%) can result in a significantly increased plasma AUC0-∞ and
hepatic uptake activity. In rats, rifampin-impaired hepatic uptake prolonged t1/2 of glycyrrhizin, caution should be exercised in the
of glycyrrhizin can significantly increase its systemic exposure to use of intravenous glycyrrhizin, due to its high likelihood to be a
glycyrrhizin (Fig. 4). Glomerular-filtration-based renal excretion victim in DDIs. This DDI information facilitates ensuring safe
of glycyrrhizin is slow due to extensive protein binding in glycyrrhizin-including combination therapies for liver diseases. To
plasma. Quantitative analysis using the PBPK model suggests a prevent such drug-glycyrrhizin interactions, plasma concentra-
high likelihood for glycyrrhizin to be a victim of hepatic DDIs tions of both glycyrrhizin and co-administered dual inhibitors of
when co-medicated with potent dual inhibitors of OATP1B1/1B3 OATP1B1/1B3 should be monitored and their dosages optimized
(Fig. 4). accordingly. OATP1B1 and OATP1B3 can compensate for the lack
The OATP1B1/1B3-mediated hepatic uptake governs systemic of each other. So, coadministration with a selective inhibitor of
clearance of and systemic exposure to glycyrrhizin. Given that OATP1B1 or OATP1B3 may not lead to significant changes in level
there are many dual OATP1B1/1B3 inhibitors (including the direct- of systemic exposure to glycyrrhizin.

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Fig. 4 Potential of intravenous glycyrrhizin as the victim in DDIs. Observed (dots) and PBPK model-simulated (lines) plasma concentration-
time profiles of glycyrrhizin in rifampin-untreated (control) and rifampin-treated rats that intravenously received glycyrrhizin at 2.6 mg/kg (a),
such plasma concentration-time profiles in humans who received a 12-min intravenous infusion of glycyrrhizin at 40 (in green), 80 (in blue),
and 120 (in red) mg/person (b), and PBPK model-predicted influence of impaired hepatic OATP1B1/1B3 activities on levels of systemic
exposure to glycyrrhizin (c and d). Chemical structure and comparative elimination routes of glycyrrhizin are shown in panel (e). The plasma
levels of glycyrrhizin were prospectively predicted under a 12-min i.v. infusion of glycyrrhizin at 120 mg/person. The assumption, used as a
worst-case estimate, was that the inhibition of OATP1B1/1B3 was constant over time. Sustaining the impairment of OATP1B1/1B3 activities by
the inhibitory perpetrator depends on the perpetrator’s inhibition potency and pharmacokinetics (the unbound plasma concentrations and
elimination t1/2). The observed human plasma concentration data of glycyrrhizin were digitalized from a publication by Yamamura et al. [148]
with permission of Elsevier and APhA. Glu glucuronosyl. (Reprinted from Dong et al., 2018 [37] with permission of John Wiley and Sons).
PKC evaluation for an herbal-synthetic medicine combination PKC investigation considers all interacting proteins that are related
Drugs in a combination therapy, particularly for multifactorial to the combination therapy and highlighted for DDIs, while the
diseases, can have distinct mechanisms of action and exert traditional investigation of natural product–drug interaction often
enhanced pharmacodynamic effect. To ensure such therapeutic focuses on one or a few of interacting proteins.
benefit, a high degree of PKC within the combination therapy is As a life-threatening organ dysfunction caused by a dysregu-
desired, i.e., absence of serious pharmacokinetic DDI among the lated host response to infection, sepsis is a critical condition, for
co-administered drugs. In China, growing evidence shows that which treatment guideline and expert consensuses in China
incorporating herbal medicines into synthetic drug-based thera- recommend adding the Chinese herbal medicine XueBiJing (an
pies for multifactorial diseases delivers therapeutic benefits intravenous five-herb injection) to antibiotic-based sepsis care
[9–12, 98, 99]. However, pharmacokinetic natural product–drug [124–127]. Because infection is the triggering event in sepsis,
interactions are a widely recognized issue that may negate such prompt initiation of appropriate antibiotic therapies to eradicate
benefits. Therefore, a drug-combination pharmacokinetic the pathogens is a cornerstone of sepsis care [128]. Meanwhile,
approach to assessing degree of PKC for an herbal medicine in attenuating the host response to infection is also significant and
combination with synthetic drugs was proposed to provide needs to be promptly initiated. However, search for synthetic
evidence to guide clinical decision on such combination therapies therapeutic agents for modulating the host response has been
[24]. So far, more commonly known is the evaluation of unsuccessful [129–131]. Combining XueBiJing with conventional
pharmacokinetic natural product–drug interactions, which mostly sepsis care was found to further reduce 28-day mortality of
seeks to identify natural products (like grapefruit juice and St. patients with sepsis and incidence of complications and
John’s wort) that can perpetrate therapeutically significant DDIs improves prognosis, with low incidence of adverse effects
with synthetic drugs. Although the recently proposed assessment [12, 132]. Pharmacological studies suggest that XueBiJing could
of PKC degree for a therapeutically promising herbal medicine/ modulate the septic response by inhibiting the uncontrolled
synthetic drug combination follows the same mechanistic basis of release of inflammatory mediators, relieving an early over-
DDI, it differs in some aspects. The PKC investigation seeks to abundant innate immune response and potentially cumulative
define the degree of PKC between the herbal medicine and the immunosuppression, attenuating the crosstalk between inflam-
co-administered synthetic drugs and to provide mechanistic mation and coagulation, protecting endothelial cells, and
evidence for any DDI risks if existing within the combination maintaining physiological functions of vital organs
therapy. In the PKC investigation, the test herbal medicine (like the [18–20, 133–135]. The therapeutic effects of XueBiJing are
test co-administered synthetic drugs) is evaluated for its potential distinct from and complementary to the antibiotic therapy.
both as perpetrator and victim for DDIs, because it is also regarded Despite its extensive use in sepsis care (over 600,000 patients
as therapeutic. In contrast, the test natural product is usually not yearly in China), report on DDIs with XueBiJing is scarce; this
considered therapeutic in natural product–drug interaction may be attributed to under-recognition, under-reporting, and
studies, and so is evaluated for its potential as perpetrator only, under-researching of such DDIs. Many antibiotics have high
(and not as victim) of the DDIs, with the goal to avoid or minimize potential for DDIs, particularly in critically ill patients who are
therapeutic failure of synthetic medicines. In addition, to support predisposed to DDIs due to multi-drug usage and who often
decision-making regarding clinical use of a drug combination, the present with organ dysfunction and multiple comorbidities

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Fig. 5 Elements of pharmacokinetic compatibility (PKC) evaluation within combination therapy of XueBiJing and antibiotics for sepsis care.
[136–138]. Given these factors, as well as complex chemical were selected for the drug-combination pharmacokinetic investi-
composition of and many bioactive constituents present in gation. No XueBiJing compound could pair, as perpetrator, with
XueBiJing, it became important to evaluate systematically the the antibiotics. Although some antibiotics could, due to their
PKC degree of the XueBiJing/antibiotics combination therapy. inhibition of UGT2B15, OAT1/2 and/or OATP1B3, pair with
The PKC investigation, considering potential for both XueBiJing- senkyunolide I, tanshinol and salvianolic acid B, the potential
antibiotic interactions (perpetrated by XueBiJing) and antibiotic- interactions (resulting in increased systemic exposure) were likely
XueBiJing interactions (perpetrated by the antibiotic), involved desirable due to these XueBiJing compounds’ low baseline
evaluation of the therapy’s PKC degree and identification of DDI exposure levels. Inhibition of aldehyde dehydrogenase (ALDH)
risks in the combination [24]. The drug-combination pharmaco- by seven antibiotics (i.e., imipenem, meropenem, ceftazidime,
kinetic investigation required: (1) a wealth of data on the penicillin, ampicillin, oxacillin, and flucloxacillin) probably led to
pharmacokinetics/disposition of XueBiJing and antibiotics and undesirable reduction of systemic exposure to protocatechuic
their DDI liabilities and (2) a method for data processing. Data on acid from XueBiJing. The XueBiJing/antibiotic combination
human pharmacokinetics of XueBiJing compounds that were exhibited a high degree of PKC at clinically relevant doses, with
bioavailable for DDIs were obtained from our earlier multi- a PKC index of 0.94, which supports concurrent use of the two
compound pharmacokinetic investigations of the injection. types of medicines in sepsis care. Figure 6 depicts this evaluation
Literature mining was performed to identify antibiotics used for of PKC degree of combination therapy of XueBiJing and
sepsis care in China and to obtain data on their pharmacokinetics/ antibiotics. Although the early identification and treatment of
disposition and DDI liabilities, as well as data on DDI liabilities of sepsis is desirable, prompt administration of all the necessary
XueBiJing and its herbal compounds. In addition, in vitro studies medications increases the drug interaction risk. For optimal sepsis
were performed to obtain additional required data on DDI care, a high degree of PKC is desirable not only between XueBiJing
potential of the XueBiJing compounds, and of the antibiotics, by and antibiotics but also between XueBiJing and other medicines
modulating drug metabolizing enzymes and drug transporters. and among different types of synthetic medicine. The preceding
Data processing was then performed in steps, i.e., pairing the drug-combination pharmacokinetic approach can be applied to
compounds, assessing the desirability of the pair-associated DDIs investigate other drug combination therapies.
and estimating PKC index (ranging from 0 to 1) of the
combination therapy. A high PKC index (close to 1) represents a
high degree of PKC for the combination therapy, i.e. with a low OUTLOOK
undesirable DDI risk, whereas a low PKC index indicates a low Despite the many advances and successes described in this
degree of PKC, with a high undesirable DDI risk. Figure 5 Review, only a limited numbers of Chinese herbal medicines have
summarizes the elements considered in evaluating the PKC of been extensively investigated and the impact of pharmacokinetic
the XueBiJing/antibiotic combination therapy. Low DDI potential research on the modernization of Chinese traditional medicine is
indicated by static-mechanistic-model-based investigation usually still limited owing to the sophistication, expertise, extensive
correlates with low clinical DDI potential, but high interaction experimental work, high cost, and long study period required. We
potential indicated by such investigation does not necessarily believe that this situation is changing as pharmacokinetic research
translate to high clinical DDI potential. To this end, only the is increasingly recognized as a powerful and versatile tool to help
identified undesirable interactions with high potential would be identify therapeutically important constituents of complex Chi-
further investigated by performing PBPK model-based prediction nese herbal medicines and develop herbal medicines for use as or
and, if necessary, relevant clinical DDI studies. in combination therapies of multifactorial diseases by acting on
By integrating informatics-based approach with experimental multiple targets in concert.
approach and by developing a compound pair-based method for More technological advances and broader studies are needed in
data processing, the PKC degree of XueBiJing/antibiotic combina- multi-compound pharmacokinetic research on the Chinese herbal
tion therapy was systematically evaluated to guide clinical medicine to enhance our ability to identify the medicine’s
decision on XueBiJing/antibiotic combination for sepsis care [24]. important constituents that are together responsible for the
To reflect clinical reality, 45 antibiotics commonly used in sepsis therapeutic action and/or adverse effect of the medicine.
care in China and 12 XueBiJing compounds bioavailable for DDIs Recently, abundant high-quality data exist and are searchable;

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Fig. 6 A schematic overview of evaluation of PKC degree of combination therapy of XueBiJing and antibiotics and the high degree of
PKC supports concurrent use of the two types of medicines in sepsis care. A1‒A45, 45 antibiotics commonly used in sepsis care in China
(see Ref. [24] for the detailed information); X1‒X12, 12 major XueBiJing compounds, unchanged and metabolized, that are bioavailable for
drug DDIs and bioactive for sepsis care (see Ref. [24] for the detailed information). (Reprinted from Li et al., 2019 [24] with permission of Acta
Pharm Sin B).
understanding of in vitro and in vivo methodology continues to unchanged constituents owing to intestinal absorption (particu-
improve; and computational power continues to increase. All larly in the upper gastrointestinal tract), loss of the unchanged
these have boosted drug discovery, including the ability to constituents owing to metabolism by the intestinal enzymes (such
identify drug candidates with appropriate pharmacokinetic as lactase-phlorizin hydrolase) or the microbiota, appearance of
properties [139, 140]. By utilizing artificial intelligence/machine the metabolites owing to these intestinal metabolism, loss of the
learning, the pharmacokinetic properties and overall profiles of metabolites owing to intestinal absorption or further metabolism
numerous constituents can be predicted for an herbal medicine in by the microbiota, and appearance of the metabolites owing to
a more high-throughput and cost-effective manner than tradi- biliary excretion of the conjugated metabolites (most often
tional methods. Rational and effective integration of the artificial glucuronides) [143]. After intravenously dosing an herbal injection,
intelligence-based predictions with various experimental measure- the intestine-luminal exposure to herbal compounds is initiated by
ments can fuel the multi-compound pharmacokinetic research on biliary excretion of the herbal compounds (unchanged and
complex herbal medicines. Initiatives to incorporate artificial metabolized) and occasionally by intestinal excretion of such
intelligence into pharmacokinetic prediction of herbal compounds compounds. The intestine-luminal exposure via intravenous
and medicines are already underway and the main questions are administration is normally much lower than that via oral
how to best utilize the technique and how to evaluate the benefit administration. In addition, the intestine-luminal exposure to
of its applications. One of the challenges posed in this field is lack herbal compounds is influenced by many factors, including
of high-quality experimental data. physicochemical properties of the herbal compounds, expression
In the multi-compound pharmacokinetic research, all types of and function of the intestinal enzymes and transporters and the
body exposure that are relevant to the therapeutic action and/or interplay of these proteins, thickness and pH of mucus, intestinal
adverse effect of an herbal medicine should be investigated for tissue structure, composition and function of the intestinal
the medicine’s constituents. Given that the human intestinal microbiota, DDI, gene variants, etc. It is generally thought that
microbiota is integral to the physiology of its host [63, 64] and is a drug compounds most accessible to the intestinal microbiota are
major source of variability in pharmacokinetics of and response to those that are orally administered but not absorbed in the upper
many drugs [141, 142], intestine-luminal exposure to the herbal gastrointestinal tract. However, after orally dosing Gancao-
compounds after dosing an herbal medicine should be assessed containing medicine, the compounds that exhibit significant
to determine the compounds’ access to the microbiota. Tradi- colon-intestinal exposure are the microbial metabolites glycyr-
tionally, pharmacokinetic investigations have focused on systemic rhetic acid and 24-hydroxyglycyrrhetic acid, rather than the
exposure to the drugs and have mostly ignored the intestine- respective unabsorbed parent constituents glycyrrhizin and
luminal exposure and the significant direct and indirect impacts of licorice saponin G2, which appear not to occur in the colon [47].
the intestinal microbiota on the systemic exposure of drugs. The Assessment of human intestine-luminal exposure to herbal
intestine-luminal exposure to herbal compounds after an orally medicines is usually based on analysis of the feces samples, but
dosed herbal medicine involves multiple elements: passage of the further investigating the exposure is difficult in healthy volunteer
unchanged constituents through the digestive tract, loss of the and patient studies. Animal models can be informative but have

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limited translational potential due to significant interspecies toxic herbs, as well as interacting and/or therapeutically active
variations in the intestinal microbiota. Therefore, human compounds of the combinations’ other component herbs. The
microbiota-associated animal models have been used widely in identified compounds are investigated for the disposition factors
intestinal microbiome research [144–146]. We have started to governing their levels of body exposure, the pharmacokinetic
utilize human microbiota-associated rats in intestine-luminal differences among them, and the simultaneous accessibility to
exposure studies of herbal medicines. Overall, current under- their respective targets. The drug-combination pharmacokinetic
standing of intestine-luminal exposure to herbal medicines is approach is used to evaluate PKC degrees of combinations for
incomplete and there are questions still to be answered. possible toxicity antagonism that counteracts the toxic effect and
After the major exposed compounds are identified for an herbal for possible efficacy synergism that reduces the dosage of the toxic
medicine, two important aspects need to be further investigated, herb; the approach is also used to evaluate the potential for and
particularly for those that are pharmacologically and/or toxicolo- toxicological outcome of pharmacokinetic DDIs that result in
gically active, i.e., (1) effective modulation of their body exposure possible toxicity antagonism. The pharmacokinetic research is to
levels and (2) their in vivo access to the associated targets. These support elucidating potential mechanisms of JianduPeiwu and
aspects are seldom investigated in traditional pharmacokinetic efficacy–toxicity relationship of the herbs in combinations and
research, but can influence the medicine’s therapeutic outcome. serves as a translational discipline. The whole project is multi-
Understanding how the exposure levels of active herbal disciplinary and aims to develop rational strategy for safe and
compounds can be effectively modulated is important for therapeutically effective use of toxic Chinese herbs in clinics.
ensuring effectiveness of an herbal medicine, by optimally Over the past decade, great advances have been achieved in
matching the compounds’ pharmacokinetic concentrations (after the theory, methodology, techniques, and requirements of,
dosing the medicine) to their respective therapeutic concentra- together with their applications in, pharmacokinetic research on
tions, or for avoiding occurrence of adverse effect of the medicine, Chinese herbal medicines, which has become an emerging field in
by containing the pharmacokinetic concentrations not to exceed pharmacokinetics. This is a great window of opportunity for the
the respective toxic concentrations. Meanwhile, understanding modernization of Chinese traditional medicine to capitalize on the
whether the exposure levels of the major active herbal pharmacokinetic approaches, with the valuable ultimate goal of
compounds could be significantly modulated is vital for evaluating ‘more effective and safe herbal medicines available to patients’.
potential for the medicine to be a victim in a DDI. Our pioneering
investigations have involved modulating levels of systemic
exposure to several herbal compounds [36, 37, 147]. In traditional AUTHOR CONTRIBUTIONS
pharmacokinetic investigations, drugs are evaluated for systemic C.L. wrote the manuscript. W.J., J.Y., C.C., and O.E.O. contributed to the writing of the
exposure and associated disposition, but little is known about manuscript.
their further access to the therapeutic/toxic targets. There are
biological barriers for drug molecules moving from the systemic
circulation to the locus of action, so it is important to under- FUNDING
standing the physiological structures of the target tissues at This work was funded by grants from the National Natural Science Foundation of
China (82192912 and 81673582), Innovation Team and Talents Cultivation Program of
cellular level. Revealing how pseudoaldosterogenic glycyrrhetic
National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202009), and
acid and 24-hydroxyglycyrrhetic acid access the renal 11β-HSD2 the Strategic Priority Research Program of the Chinese Academy of Sciences
allows us to identify the ‘safety belt’ for extensive use of Gancao (XDA12050306).
and Gancao-containing medicines in Chinese traditional medicine
and people who are susceptible to Gancao-induced pseudoaldos-
teronism (such as patients with hypoalbuminemia) [47]. ADDITIONAL INFORMATION
So far, drug-combination pharmacokinetic research on Chinese Competing interests: The authors declare no competing interests.
herbal medicines has focused mainly on identifying risks of
unintentional DDI associated with herbal medicines used as or in
combination therapies. Safe and effective combination therapies are REFERENCES
ensured by avoiding the identified risks. In practice of Chinese 1. Outline of the main points of prevention and treatment of epidemic diseases
traditional medicine, many toxic herbs are used for therapeutic with traditional Chinese medicine. Beijing J Tradit Chin Med (Beijing Zhon-
purposes, and FangjiPeiwu is used to minimize their toxicities. This gyiyao). 2014;33:910–2.
deliberate combination for minimizing herb’s toxicity (‘JianduPeiwu’ 2. Chinese National Health Commission and Chinese State Administration of Tra-
in Chinese) is another way of ensuring safe combination therapies. ditional Chinese Medicine, Diagnosis and Treatment of Adults with Coronavirus
Disease 2019 (COVID-19) (the ninth version), March 15th, 2022 http://
Based on the QiqingHehe principle, JianduPeiwu is hypothesized to
www.nhc.gov.cn/yzygj/s7653p/202203/b74ade1ba4494583805a3d2e40093d88/
involve three mechanisms of two types; they are toxicity antagon- files/ef09aa4070244620b010951b088b8a27.pdf. (accessed on 27th March, 2022)
ism, associated with ‘Xiangwei’/’Xiangsha’, that utilizes the combi- 3. Zhang BL. Traditional Chinese medicine in China’s combating of Covid-19,
nation’s other herb(s) to minimize the toxicity of the toxic herb by brimming with cultural confidence. Red Flag Manuscr (Hongqi Wengao).
counteracting the toxic effect or by reducing the level of exposure 2021;6:37–40.
to the toxic compounds via pharmacokinetic DDI and efficacy 4. Ni LQ, Chen LL, Huang X, Han CP, Xu JR, Zhang H, et al. Combating COVID-19
synergism, associated with ‘Xiangxu’ and’Xiangshi’, that decreases with integrated traditional Chinese and Western medicine in China. Acta Pharm
the dosage of the toxic herb but maintains the same efficacy while Sin B 2020;10:1149–62.
minimizing the toxicity. Last year, the National Natural Science 5. National Medical Products Administration, The notification regarding the imple-
mentation of Good Manufacturing Practice of Medical Products (version 2010),
Foundation of China approved support for a major project in
https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20110225152101646.html.
JianduPeiwu for therapeutic use of toxic Chinese herbs. The funded (Accessed 7 June 2022).
project (82192910) involves both multi-compound and drug- 6. Zhang BL, Chen CH, editors-in-chief. Modernization of Chinese medicine for
combination pharmacokinetic research (which works closely with twenty years (1996–2015). Shanghai: Shanghai Science & Technology Press;
other disciplines) and selects the commonly used toxic Chinese 2016.
medicinal herbs Euodia rutaecarpa fruit (Wuzhuyu) and Psoralea 7. National People’s Congress Standing Committee. Drug Administration Law of
corylifolia fruit (Buguzhi) and their formulated herb combinations the People’s Republic of China. Beijing: Law Press China; 2019.
(i.e., Wuzhuyu decoction, Zuojin pill, Eshen pill, and Sishen pill) for 8. Wang C, Cao B, Liu QQ, Zou ZQ, Liang ZA, Gu L, et al. Oseltamivir compared with
investigation. The multi-compound pharmacokinetic approach is the Chinese traditional therapy Maxingshigan–Yinqiaosan in the treatment of
H1N1 influenza. Ann Intern Med. 2011;155:217–25.
used as the forerunner for identification of toxic compounds of the

C Li et al.
3093
9. Li XL, Zhang J, Huang J, Ma AQ, Yang JF, Li WM, et al. A multicenter, randomized, 33. Stieger B, Mahdi ZM, Jager W. Intestinal and hepatocellular transporters: ther-
double-blind, parallel-group, placebo-controlled study of the effects of Qili apeutic effects and drug interactions of herbal supplements. Annu Rev Pharm
Qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol. Toxicol. 2017;57:399–416.
2013;62:1065–72. 34. Zhang MM, Liu XM, Li J, He L, Tripathy D. Chinese medicinal herbs to treat the
10. Shang HC, Zhang JH, Yao C, Liu BY, Gao XM, Ren M, et al. Qi-Shen-Yi-Qi dripping side-effects of chemotherapy in breast cancer patients. Cochrane Database Syst
pills for the secondary prevention of myocardial infarction: a randomised clinical Rev. 2007;18:CD004921.
trial. Evid Based Complement Altern Med. 2013;2013:738391. 35. Lam W, Bussom S, Guan FL, Jiang ZL, Zhang W, Gullen EA, Liu SH, Cheng YC. The
11. Zhang L, Li P, Xing CY, Zhao JY, He YN, Wang JQ, et al. Efficacy and safety of four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastro-
Abelmoschus manihot for primary glomerular disease: a prospective, multicenter intestinal toxicity. Sci Transl Med. 2010;2:45ra59.
randomized controlled clinical trial. Am J Kidney Dis. 2014;64:57–65. 36. Jiang RR, Dong JJ, Li XX, Du FF, Jia WW, Xu F, et al. Molecular mechanisms
12. Song YL, Yao C, Yao YM, Han H, Zhao XD, Yu KJ, et al. XueBiJing injection versus governing different pharmacokinetics of ginsenosides and potential for
placebo for critically ill patients with severe community-acquired pneumonia: a ginsenoside-perpetrated herb-drug interactions on OATP1B3. Br J Pharmacol.
randomized controlled trial. Crit Care Med. 2019;47:e735–43. 2015;172:1059–73.
13. Huang H, Ji LX, Song SY, Wang J, Wei N, Jiang M, et al. Identification of the major 37. Dong JJ, Olaleye OE, Jiang RR, Li J, Lu C, Du FF, et al. Glycyrrhizin has a high
constituents in XueBiJing injection by HPLC-ESI-MS. Phytochem Anal. likelihood to be a victim of drug-drug interactions mediated by hepatic
2011;22:330–8. OATP1B1/1B3. Br J Pharmacol. 2018;175:3486–503.
14. Sun Z, Zuo LH, Sun TW, Tang JF, Ding DL, Zhou L, et al. Chemical profiling and 38. Olaleye OE, Niu W, Du FF, Wang FQ, Xu F, Pintusophon S, et al. Inhibition of
quantification of XueBiJing injection, a systematic quality control strategy using hepatic OATP1Bs by circulating saponins from intravenous ShenMai: potential
UHPLC-Q exactive hybrid quadrupole-orbitrap high-resolution mass spectro- joint precipitants of drug interactions. Acta Pharmacol Sin. 2019;40:833–49.
metry. Sci Rep. 2017;7:16921. 39. Pintusophon S, Niu W, Duan XN, Olaleye OE, Huang YH, Wang FQ, et al. Intra-
15. Yu X, Niu W, Wang YY, Olaleye OE, Wang JN, Duan MY, et al. Novel assays for venous formulation of Panax notoginseng root extract: human pharmacokinetics
quality evaluation of XueBiJing: quality variability of a Chinese herbal injection of ginsenosides and potential for perpetrating drug interactions. Acta Phar-
for sepsis management. J Pharm Anal. 2022. https://doi.org/10.1016/ macol Sin. 2019;40:1351–63.
j.jpha.2022.01.001. 40. Li L, Zhao YS, Du FF, Yang JL, Xu F, Ren YH, et al. Intestinal absorption and
16. Yin Q, Li CS. Treatment effects of XueBiJing injection in severe septic patients presystemic elimination of various chemical constituents present in GBE50
with disseminated intravascular coagulation. Evid Based Complement Altern extract, a standardized extract of Ginkgo biloba leaves. Curr Drug Metab.
Med. 2014;2014:949254. 2012;13:494–509.
17. Wang Q, Wu X, Tong XW, Zhang ZL, Xu B, Zhou WG. XueBiJing ameliorates 41. Chen F, Li L, Xu F, Sun Y, Du FF, Ma XT, et al. Systemic and cerebral exposure to
sepsis-induced lung injury by downregulating HMGB1 and RAGE expressions in and pharmacokinetics of flavonols and terpene lactones after dosing standar-
mice. Evid Based Complement Altern Med. 2015;2015:860259. dized Ginkgo biloba leaf extracts to rats via different administration routes. Br J
18. Wang L, Liu ZY, Dong Z, Pan JY, Ma XC. Effects of XueBiJing injection on Pharmacol. 2013;170:440–57.
microcirculation in septic shock. J Surg Res. 2016;202:147–54. 42. Hu ZY, Yang JL, Cheng C, Huang YH, Du FF, Wang FQ, et al. Combinatorial
19. Dong TH, Zhang GP, Dong K, Liu S, Yao YM. Research progress on mechanism of metabolism notably affects human systemic exposure to ginsenosides from
action of XueBiJing injection in the treatment of sepsis. Chin J Tradit Chin Med orally administered extract of Panax notoginseng roots (Sanqi). Drug Metab
West Med Crit Care. 2016;23:554–7. Dispos. 2013;41:1457–69.
20. Chen X, Feng YX, Shen XY, Pan GX, Fan GW, Gao XM, et al. Anti-sepsis protection 43. Li MJ, Wang FQ, Huang YH, Du FF, Zhong CC, Olaleye OE, et al. Systemic
of XueBiJing injection is mediated by differential regulation of pro- and anti- exposure to and disposition of catechols, derived from Salvia miltiorrhiza roots
inflammatory Th17 and T regulatory cells in a murine model of polymicrobial (Danshen), after intravenous dosing DanHong injection in human subjects, rats,
sepsis. J Ethnopharmacol. 2018;211:358–65. and dogs. Drug Metab Dispos. 2015;43:679–90.
21. Cheng C, Lin JZ, Li L, Yang JL, Jia WW, Huang YH, et al. Pharmacokinetics and 44. Cheng C, Du FF, Yu K, Xu F, Wang FQ, Li L, et al. Pharmacokinetics and dis-
disposition of monoterpene glycosides derived from Paeonia lactiflora roots position of circulating iridoids and organic acids after intravenous administra-
(Chishao) after intravenous dosing of antiseptic XueBiJing injection in human tion of ReDuNing injection in rats. Drug Metab Dispos. 2016;44:1853–8.
subjects and rats. Acta Pharm Sin. 2016;37:530–44. 45. Liu XW, Yang JL, Jia WW, Wen Q, Niu W, Duan XN, et al. Human pharmacoki-
22. Li XX, Cheng C, Wang FQ, Huang YH, Jia WW, Olaleye OE, et al. Pharmacokinetics netics of ginkgo terpene lactones and impact of carboxylation in blood on their
of catechols in human subjects intravenously receiving XueBiJing injection, an platelet-activating factor antagonistic activity. Acta Pharmacol Sin.
emerging antiseptic herbal medicine. Drug Metab Pharmacokinet. 2016;31:95–8. 2018;39:1935–46.
23. Zhang NT, Cheng C, Olaleye OE, Sun Y, Li L, Huang YH, et al. Pharmacokinetics- 46. Zhang HY, Niu W, Olaleye OE, Du FF, Wang FQ, Huang YH, et al. Comparison of
based identification of potential therapeutic phthalides from XueBiJing, a Chi- intramuscular and intravenous pharmacokinetics of ginsenosides in humans
nese herbal injection used in sepsis management. Drug Metab Dispos. after dosing XueShuanTong, a lyophilized extract of Panax notoginseng roots. J
2018;46:823–34. Ethnopharmacol. 2020;253:112658.
24. Li J, Olaleye OE, Yu X, Jia WW, Yang JL, Lu C, et al. High degree of pharmaco- 47. Lan XF, Olajide OE, Du FF, Yang JL, Shi YH, Yang W, et al. Pharmacokinetics-
kinetic compatibility exists between the five-herb medicine XueBiJing and based identification of pseudoaldosterogenic compounds originating from
antibiotics comedicated in sepsis care. Acta Pharm Sin B 2019;9:1035–49. Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule. Acta
25. Zheng R, Wang H, Liu Z, Wang XH, Li J, Lei X, et al. A real-world study on adverse Pharmacol Sin. 2021;42:2155–72.
drug reactions to XueBiJing injection: hospital intensive monitoring based on 93 48. Koltermann A, Hartkorn A, Koch E, Furst R, Vollmar AM, Zahler S. Ginkgo biloba
hospitals (31,913 cases). Ann Transl Med 2019;7:117. extract EGb761 increases endothelial nitric oxide production in vitro and in vivo.
26. Lu T, Yang JL, Gao XM, Chen P, Du FF, Sun Y, et al. Plasma and urinary tanshinol Cell Mol Life Sci. 2007;64:1715–22.
from Salvia miltiorrhiza (Danshen), can be used as pharmacokinetic markers for 49. Wu YZ, Li SQ, Cui W, Zu XG, Wang FF, Du J. Ginkgo biloba extract improves
cardiotonic pills, a cardiovascular herbal medicine. Drug Metab Dispos. coronary blood flow in patients with coronary artery disease: role of endothelial-
2008;36:1578–86. dependent vasodilation. Planta Med. 2007;73:624–8.
27. Liu HF, Yang JL, Du FF, Gao XM, Ma XT, Huang YH, et al. Absorption and 50. Mashayekh A, Pham DL, Yousem DM, Dizon M, Barker PB, Lin DDM. Effects of
disposition of ginsenosides after oral administration of Panax notoginseng Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion
extract to rats. Drug Metab Dispos. 2009;37:2290–8. imaging: a pilot study. Neuroradiology 2011;53:185–91.
28. Li C. Multi-compound pharmacokinetic research on Chinese herbal medicines: 51. Ou HC, Lee WJ, Lee IT, Chiu TH, Tsai KL, Lin CY, et al. Ginkgo biloba extract
approach and methodology. China J Chin Mater Med. 2017;42:607–17. attenuates oxLDL-induced oxidative functional damages in endothelial cells. J
29. Li C, Yang JL, Cheng C, Jia WW, Olaleye OE. Pharmacokinetic research on Chi- Appl Physiol. 2009;106:1674–85.
nese herbal medicines. Bull Jpn China Med Assoc. 2018;33:9–14. 52. Chen JW, Chen YH, Lin FY, Chen YL, Lin SJ. Ginkgo biloba extract inhibits tumor
30. Li C, Cheng C, Jia WW, Yang JL, Yu X, Olaleye OE. Multi-compound pharmaco- necrosis factor-induced reactive oxygen species generation, transcription factor
kinetic research on Chinese herbal medicines: identifying the medicines’ activation, and cell adhesion molecule expression in human aortic endothelial
potentially therapeutic compounds and characterizing their disposition and cells. Arterioscler Thromb Vasc Biol. 2003;23:1559–66.
pharmacokinetics. Acta Pharm Sin. 2021;56:2426–46. 53. Chen JS, Huang PH, Wang CH, Lin FY, Tsai HY, Wu TC, et al. Nrf-2 mediated heme
31. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355:134–8. oxygenase-1 expression, an antioxidant-independent mechanism, contributes
32. Hermann R, Richter O. Clinical evidence of herbal drugs as perpetrators of to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract.
pharmacokinetic drug interactions. Planta Med. 2012;78:1458–77. Atherosclerosis. 2011;214:301–9.

C Li et al.
3094
54. Tsai JY, Su KH, Shyue SK, Kou YR, Yu YB, Hsiao SH, et al. EGb761 ameliorates the biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sec-
formation of foam cells by regulating the expression of SR-A and ABCA1: role of tional study. Arch Toxicol. 2019;93:3111–9.
haem oxygenase-1. Cardiovasc Res. 2010;88:415–23. 80. Morinaga O, Ishiuchi K, Ohkita T, Tian C-T, Hirasawa A, Mitamur M, et al. Isolation
55. Huang SY, Jeng C, Kao SC, Yu JJH, Liu DZ. Improved haemorrheological prop- of a novel glycyrrhizin metabolite as a causal candidate compound for pseu-
erties by Ginkgo biloba extract (Egb761) in type 2 diabetes mellitus complicated doaldosteronism. Sci Rep. 2018;8:15568.
with retinopathy. Clin Nutr. 2004;23:615–21. 81. Chapman K, Holmes M, Seckl J. 11β-hydroxysteroid dehydrogenases: intracellular
56. Luo Y, Smith JV, Paramasivam V, Burdick A, Curry KJ, Buford JP, et al. Inhibition gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013;93:1139–206.
of amyoid-β aggregation and caspase-3 activation by the Ginkgo biloba extract 82. Hunter RW, Bailey MA. Glucocorticoids and 11β-hydroxysteroid dehydrogenases:
EGb761. Proc Natl Acad Sci USA. 2002;99:12197–202. mechanisms for hypertension. Curr Opin Pharmacol. 2015;21:105–14.
57. Longpré F, Garneau P, Christen Y, Ramassamy C. Protection by Egb761 against 83. Jia Beditor-in-chief. FangjiXue (Chinese Medical Formulae: Therapeutic Effects
β-amyloid-induced neurotoxicity: involvement of NF-κB, SIRT1, and MAPKs and Use). Beijing, China Press of Traditional Chinese Medicine; 2016. Chinesey
pathways and inhibiton of amyloid fibril formation. Free Radic Biol Med. 84. Morphy R, Kay C, Rankovic Z. From magic bullets to designed multiple ligands.
2006;41:1781–94. Drug Discov Today. 2004;9:641–51.
58. Tchantchou F, Xu Y, Wu YJ, Christen Y, Luo Y. EGb761 enhances adult hippo- 85. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat
campal neurogenesis and phosphorylation of CREB in transgenic mouse model Chem Biol. 2008;4:682–90.
of Alzheimer’s disease. FASEB J. 2007;21:2400–8. 86. Mestres J, Gregori-Puigjanć E. Conciliating binding efficiency and poly-
59. Saleem S, Zhuang H, Biswal S, Christen Y, Doré S. Ginkgo biloba extract neuro- pharmacology. Trends Pharmacol Sci. 2009;30:470–4.
protective action is dependent on heme oxygenase 1 in ischemic reperfusion 87. Peters J-U. Polypharmacology—foe or friend? J Med Chem. 2013;56:8955–71.
brain injury. Stroke. 2008;39:3389–96. 88. Anighoro A, Bajorath J, Rastelli G. Polypharmacology: challenges and opportu-
60. Strømgaard K, Nakanishi K. Chemistry and biology of terpene trilactones from nities in drug discovery. J Med Chem. 2014;57:7874–87.
Ginkgo biloba. Angew Chem Int Ed. 2004;43:1640–58. 89. Korcsmáros T, Szalay MS, Böde C, Kovács IA, Csermely P. How to design multi-
61. Blumenthal M. The ABC Clinical Guide to Herbs. New York: Thieme; 2003. target drugs. Expert Opin Drug Discov. 2007;2:799–808.
p. 185–200. 90. Costantino L, Barlocco D. Designed multiple ligands: basic research vs clinical
62. van Beek TA, Montoro P. Chemical analysis and quality control of Ginkgo biloba outcomes. Curr Med Chem. 2012;19:3353–87.
leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 2009;1216:2002–32. 91. Proschak E, Stark H, Merk D. Polypharmacology by design: a medicinal chemist’s
63. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. perspective on multitargeting compounds. J Med Chem. 2019;62:420–44.
N Engl J Med. 2016;375:2369–79. 92. Lehár J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, et al. Syner-
64. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat gistic drug combinations tend to improve therapeutically relevant selectivity.
Rev Microbiol. 2021;19:55–71. Nat Biotechnol. 2009;27:659–66.
65. Jia W, Li HK, Zhao LP, Nicholson JK. Gut microbiota: a potential new territory for 93. Jia J, Zhu F, Ma XH, Cao ZW, Li YX, Chen YZ. Mechanisms of drug combinations:
drug targeting. Nat Rev Drug Discov. 2008;7:123–9. interaction and network perspective. Nat Rev Drug Discov. 2009;8:111–28.
66. He MQ, Shi BY. Gut microbiota as a potential target of metabolic syndrome: the 94. Sun W, Sanderson PE, Zheng W. Drug combination therapy increases successful
role of probiotics and prebiotics. Cell Biosci. 2017;7:54. drug repositioning. Drug Discov Today. 2016;21:1189–95.
67. Roberts AB, Gu XD, Buffa JA, Hurd AG, Wang ZN, Zhu WF, et al. Development of 95. Shyr ZA, Cheng YS, Lo DC, Zheng W. Drug combination therapy for emerging
a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. viral diseases. Drug Discov Today. 2021;26:2367–76.
Nat Med. 2018;24:1407–17. 96. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hyper-
68. Zeng X, Deng YH, Feng Y, Liu YM, Yang L, Huang Y, et al. Pharmacokinetics and tension. J Am Soc Hypertens. 2010;4:90–8.
safety of ginsenoside Rd following a single or multiple intravenous dose in 97. Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in
healthy Chinese volunteers. J Clin Pharmacol. 2010;50:285–92. the post-genomic era. Nat Biotechnol. 2012;30:679–92.
69. Lu JL, Zeng XS, Zhou X, Yang JL, Ren LL, Long XY, et al. Molecular basis 98. Zhang MM, Liu XM, Li J, He L, Tripathy D. Chinese medicinal herbs to treat the
underlying hepatobiliary and renal excretion of phenolic acids of Salvia mil- side-effects of chemotherapy in breast cancer patients. Cochrane Database Syst
tiorrhiza roots (Danshen). Front Pharmacol. 2022;13:911982. Rev. 2007;18:CD004921.
70. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, et al. 99. Lam W, Bussom S, Guan FL, Jiang ZL, Zhang W, Gullen EA, et al. The four-herb
Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab. Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal
2012;3:125–38. toxicity. Sci Transl Med. 2010;2:45ra59.
71. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, 100. Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions:
an active component of liquorice roots, and replication of SARS-associated challenges and opportunities for improved predictions. Drug Metab Dispos.
coronavirus. Lancet. 2003;361:2045–6. 2014;42:301–17.
72. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, et al. 101. Bailey DG, Spence JD, Munoz C, Arnold JMO. Interaction of citrus juices with
Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab. felodipine and nifedipine. Lancet. 1991;37:268–9.
2012;3:125–38. 102. Bailey DG, Arnold JMO, Bend JR, Tran LT, Spence JD. Grapefruit juice-felodipine
73. Kato H, Kanaoka M, Yano S, Kobayashi M. 3-Monoglucuronyl-glycyrrhetinic acid interaction: reproducibility and characterization with the extended release drug
is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin formulation. Br J Clin Pharmacol. 1995;40:135–40.
Endocrinol Metab. 1995;80:1929–33. 103. Pirmohanmed M. Drug-grapefruit juice interactions: two mechanisms are clear
74. Ohtake N, Kido A, Kubota K, Tsuchiya N, Morita T, Kase Y, et al. A possible but individual responses vary. BMJ. 2013;346:f1.
involvement of 3-monoglucuronyl-glycyrrhetinic acid, a metabolite of glycyr- 104. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart transplant
rhizin (GL), in GL-induced pseudoaldosteronism. Life Sci. 2007;80:1545–52. rejection due to Saint John’s wort. Lancet. 2000;355:548–9.
75. Makino T, Ohtake N, Watanabe A, Tsuchiya N, Imamura S, Iizuka S, et al. Down- 105. Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffmann MW, Klempnauer J.
regulation of a hepatic transporter multidrug resistance-associated protein 2 is Profound drop of cyclosporine a whole blood trough levels caused by St. John’s
involved in alteration of pharmacokinetics of glycyrrhizin and its metabolites in wort (Hypericum perforatum). Transplantation. 2000;69:2229–30.
a rat model of chronic liver injury. Drug Metab Dispos. 2008;36:1438–43. 106. Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug interaction
76. Makino T, Okajima K, Uebayashi R, Ohtake N, Inoue K, Mizukami H. 3- between St. John’s wort and cyclosporine. Ann Pharmacother. 2000;34:1013–6.
Monoglucuronyl-glycyrrhretinic acid is a substrate of organic anion transporters 107. Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United
expressed in tubular epithelial cells and plays important roles in licorice-induced States: potential adverse interactions with anticancer agents. J Clin Oncol.
pseudoaldosteronism by inhibiting 11β-hydroxysteroid dehydrogenase 2. J 2004;22:2489–503.
Pharmacol Exp Ther. 2012;342:297–304. 108. Tachjian A, Maria V, Jahangir A. Use of herbal products and potential interac-
77. Makino T. 3-Monoglucuronyl glycyrrhretinic acid is a possible marker compound tions in patients with cardiovascular diseases. J Am Coll Cardiol. 2010;55:515–25.
related to licorice-induced pseudoaldosteronism. Biol Pharm Bull. 109. Yu K, Chen F, Li C. Absorption and disposition of saponins: what do we know
2014;37:898–902. and what do we need to know? Curr Drug Metab. 2012;13:577–98.
78. Ishiuchi K, Morinaga O, Ohkita T, Tian CT, Hirasawa A, Mitamur M, et al. 18β- 110. Ramanathan MR, Penzak SR. Pharmacokinetic drug interactions with Panax
Glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseu- ginseng. Eur J Drug Metab Pharmacokinet. 2017;42:545–57.
doaldosteronism. Sci Rep. 2019;9:1587. 111. Awortwe C, Makiwane M, Reuter H, Muller C, Louw J, Rosenkranz B. Critical
79. Takahashi K, Yoshino T, Maki Y, Ishiuchi K, Namiki T, Ogawa-Ochiai K, et al. evaluation of causality assessment of herb-drug interactions in patients. Br J Clin
Identification of glycyrrhizin metabolites in humans and of a potential Pharmacol. 2018;84:679–93.

C Li et al.
3095
112. Malati CY, Robertson SM, Hunt JD, Chairez C, Alfaro RM, Kovacs JA, et al. 131. Steinhagen F, Schmidt SV, Schewe JC, Peukert K, Klinman DM, Bode C. Immu-
Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P- notherapy in sepsis—brake or accelerate? Pharmacol Ther. 2020;208:107476.
gp) activity in healthy participants. J Clin Pharmacol. 2012;52:932–9. 132. Li CY, Wang P, Zhang L, Li M, Lei X, Liu S, et al. Efficacy and safety of XueBiJing
113. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y-Y, et al. injection (a Chinese patent) for sepsis: a meta-analysis of randomized controlled
Clinical assessment of effects of botanical supplementation on cytochrome trials. J Ethnopharmacol. 2018;224:512–21.
P450 phenotypes in the elderly. Drug Aging. 2005;22:525–39. 133. Liu YC, Yao FH, Chai YF, Dong N, Sheng ZY, Yao YM. XueBiJing injection pro-
114. Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ, et al. Hepatic motes M2 polarization of macrophages and improves survival rate in septic
uptake of cholecystokinin octapeptide by organic anion-transporting polypep- mice. Evid Based Complement Altern Med. 2015;2015:352642.
tides OATP4 and OATP8 of rat and human liver. Gastroenterology. 134. Li AL, Li J, Bao YH, Yuan DS, Huang ZW. XueBiJing injection alleviates cytokine-
2001;121:1185–90. induced inflammatory liver injury in CLP-induced septic rats through induction
115. Ishiguro N, Maeda K, Kishimoto W, Saito A, Harada A, Ebner T, et al. Predominant of suppressor of cytokine signaling 1. Exp Ther Med. 2016;12:1531–6.
contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II 135. Li TT, Qian YM, Miao ZL, Zheng PY, Shi T, Jiang XR, et al. XueBiJing injection
receptor antagonist, in humans. Drug Metab Dispos. 2006;34:1109–15. alleviates Pam3CSK4-induced inflammatory response and protects mice from
116. Letschert K, Faulstich H, Keller D, Keppler D. Molecular characterization and sepsis caused by methicillin-resistant staphylococcus aureus. Front Pharmacol.
inhibition of amanitin uptake into human hepatocytes. Toxicol Sci. 2020;11:104.
2006;91:140–9. 136. Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the inten-
117. Zhang AJ, Wang CY, Liu Q, Meng Q, Peng JY, Sun HJ, et al. Involvement of sive care unit: focus on drug interactions. Clin Pharmacokinet. 2001;40:833–68.
organic anion-transporting polypeptides in the hepatic uptake of dioscin in rats 137. Pereira JM, Paiva JA. Antimicrobial drug interactions in the critically ill patients.
and humans. Drug Metab Dispos. 2013;41:994–1003. Curr Clin Pharmacol. 2013;8:25–38.
118. Komoroski BJ, Zhang S-M, Cai H-B, Hutzler M, Frye R, Tracy TS, et al. Induction 138. Uijtendaal EV, van Harssel LL, Hugenholtz GW, Kuck EM. Zwart-van Rijkom JE,
and inhibition of cytochromes P450 by the St. John’s wort constituent hyper- Cremer OL, et al. Analysis of potential drug-drug interactions in medical
forin in human hepatocyte cultures. Drug Metab Dispos. 2004;32:512–8. intensive care unit patients. Pharmacotherapy. 2014;34:213–9.
119. Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. 139. Danishuddin, Kumar V, Faheem M, Lee KW. A decade of machine learning-based
and its bioactive compounds. Phytother Res. 2008;22:709–24. predictive models for human pharmacokinetics: advances and challenges. Drug
120. Li JY, Cao HY, Liu P, Cheng GH, Sun MY. Glycyrrhizic acid in the treatment of liver Discov Today. 2022;27:529–37.
diseases: literature review. Biomed Res Int. 2014;2014:872139. 140. Wright MR. Opportunities and considerations in the application of artificial intel-
121. Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, et al. The long ligence to pharmacokinetic prediction. Methods Mol Biol. 2022;2390:461–82.
term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 141. Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP. Gut reactions:
1997;79:1494–500. breaking down xenobiotic-microbiome interactions. Pharmacol Rev.
122. Expert Committee for Prevention and Management of Liver Inflammation, 2019;71:198–224.
Chinese Society of Infectious Diseases. Consensus statement by the expert 142. Hitchings R, Kelly L. Predicting and understanding the human microbiome’s
committee for prevention and management of liver inflammation in China. Chin impact on pharmacology. Trends Pharmacol Sci. 2019;40:495–505.
J Hepatol. 2014;22:94–103. 143. Wang YY, Chu ZX, Yang JL, Olaleye OE, He RR, Li MZ, et al. Poteial health benefits
123. Expert Committee on Clinical Application of Glycyrrhizin Preparation in the of resveratrol: a pharmacokinetics-caused conundrum. Chin J Clin Pharmacol
Treatment of Liver Diseases. Expert consensus on clinical application of gly- Ther. 2021;26:931–54. Chinese
cyrrhizin preparation in the treatment of liver diseases. J Clin Hepatol. 144. Hintze KJ, Cox JE, Rompato G, Benninghoff AD, Ward RE, Broadbent J, et al.
2016;32:844–52. Broad scope method for creating humanized animal models for animal health
124. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, and disease research through antibiotic treatment and human fecal transfer.
et al. The third international consensus definitions for sepsis and septic shock Gut Microbes. 2014;5:18391.
(sepsis-3). J Am Med Assoc. 2016;315:801–10. 145. Arrieta M-C, Walter J, Finlay BB. Human microbiota-associated mice: a model
125. Cao Y, Chai YF, Deng Y, Fang BJ, Liu MH, Lu ZQ, et al. Chinese guidelines for with challenges. Cell Host Microbe. 2016;19:575–8.
emergency management of sepsis and septic shock 2018. J Clin Emerg. 146. Staley C, Kaiser T, Beura LK, Hamilton MJ, Weingarden AR, Bobr A, et al. Stable
2018;19:567–88. engraftment of human microbiota into mice with a single oral gavage following
126. Zhao GZ, Chen RB, Li B, Guo YH, Xie YM, Liao X, et al. Clinical practice guideline antibiotic conditioning. Microbiome. 2017;5:87.
on traditional Chinese medicine therapy alone or combined with antibiotics for 147. Jia WW, Du FF, Liu XW, Jiang RR, Xu F, Yang JL, et al. Renal tubular secretion of
sepsis. Ann Transl Med. 2019;7:122. tanshinol: molecular mechanisms, impact on its systemic exposure, and pro-
127. Cao Y, Chai YF, Chen FY, Chen XH, Chen YG, Deng Y, et al. Chinese emergency pensity for dose-related nephrotoxicity and for renal herb-drug interactions.
medicine expert consensus on diagnosis and treatment of sepsis complicated Drug Metab Dispos. 2015;43:669–78.
with disseminated intravascular coagulation. Zhonghua Wei Zhong Bing Ji Jiu Yi 148. Yamamura Y, Kawakami J, Santa T, Kotaki H, Uchino K, Sawada Y, et al. Phar-
Xue. 2017;29:577–80. macokinetic profile of glycyrrhizin in healthy volunteers by a new high-
128. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving performance liquid chromatographic method. J Pharm Sci. 1992;81:1042–6.
sepsis campaign: international guidelines for management of sepsis and septic
shock: 2016. Intensive Care Med. 2017;43:304–77.
129. Fink MP, Warren HS. Strategies to improve drug development for sepsis. Nat Rev Springer Nature or its licensor holds exclusive rights to this article under a publishing
Drug Discov. 2014;13:741–58. agreement with the author(s) or other rightsholder(s); author self-archiving of the
130. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, et al. accepted manuscript version of this article is solely governed by the terms of such
Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614. publishing agreement and applicable law.

Multi-Compound and Drug-Combination Pharmacokinetic Research On Chinese Herbal Medicines

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Keywords: Chinese herbal medicine; pharmacokinetics; multi-compound pharmacokinetic research; drug-combination

Acta Pharmacologica Sinica (2022) 43:3080–3095; https://doi.org/10.1038/s41401-022-00983-7

INTRODUCTION marketing [7]. Historically, herbal medicines were not extensively

Received: 5 August 2022 Accepted: 12 August 2022

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

Acta Pharmacologica Sinica (2022) 43:3080 – 3095

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