Pharmacokinetics

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see
chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate
of substances administered to a living organism. The substances of interest include any chemical xenobiotic
such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical
metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at
which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a
drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together
influence dosing, benefit, and adverse effects, as seen in PK/PD models.

IUPAC definition
Contents Pharmacokinetics:

Overview 1. Process of the uptake

of drugs by the body,
Metrics
the biotransformation
Pharmacokinetic models they undergo, the
Noncompartmental analysis distribution of the
Compartmental analysis drugs and their
metabolites in the
Single-compartment model
tissues, and the
Multi-compartmental models elimination of the
Bioavailability drugs and their
metabolites from the
LADME body over a period of
Analysis time.
Bioanalytical methods 2. Study of more such
Mass spectrometry related processes[1]
Population pharmacokinetics
Clinical pharmacokinetics
Ecotoxicology
See also
References
External links
Software
Educational centres

Overview
Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through
the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body
(e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and
routes of excretion of the metabolites of the drug.[2] Pharmacokinetic properties of chemicals are affected by
the route of administration and the dose of administered drug. These may affect the absorption rate.[3]
Models have been developed to simplify conceptualization of the
many processes that take place in the interaction between an organism
and a chemical substance. One of these, the multi-compartmental
model, is the most commonly used approximations to reality;
however, the complexity involved in adding parameters with that
modelling approach means that monocompartmental models and
above all two compartmental models are the most-frequently used.
The various compartments that the model is divided into are
commonly referred to as the ADME scheme (also referred to as
LADME if liberation is included as a separate step from absorption):

Liberation – the process of release of a drug from the

pharmaceutical formulation.[4][5] See also IVIVC.
Absorption – the process of a substance entering the blood
circulation.
Topics of Pharmacokinetics
Distribution – the dispersion or dissemination of
substances throughout the fluids and tissues of the body.
Metabolism (or biotransformation, or inactivation) – the recognition by the organism that a
foreign substance is present and the irreversible transformation of parent compounds into
daughter metabolites.
Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly
accumulate in body tissue.

The two phases of metabolism and excretion can also be grouped together under the title elimination. The
study of these distinct phases involves the use and manipulation of basic concepts in order to understand the
process dynamics. For this reason, in order to fully comprehend the kinetics of a drug it is necessary to have
detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the
characteristics of the appropriate biological membranes and the way that substances can cross them, or the
characteristics of the enzyme reactions that inactivate the drug.

All these concepts can be represented through mathematical formulas that have a corresponding graphical
representation. The use of these models allows an understanding of the characteristics of a molecule, as well as
how a particular drug will behave given information regarding some of its basic characteristics such as its acid
dissociation constant (pKa), bioavailability and solubility, absorption capacity and distribution in the organism.

The model outputs for a drug can be used in industry (for example, in calculating bioequivalence when
designing generic drugs) or in the clinical application of pharmacokinetic concepts. Clinical pharmacokinetics
provides many performance guidelines for effective and efficient use of drugs for human-health professionals
and in veterinary medicine.

Metrics
The following are the most commonly measured pharmacokinetic metrics:[6] The units of the dose in the table
are expressed in moles (mol) and molar (M). To express the metrics of the table in units of mass, instead of
Amount of substance, simply replace 'mol' with 'g' and 'M' with 'g/dm3'. Similarly, other units in the table may
be expressed in units of an equivalent dimension by scaling.
 Pharmacokinetic metrics
Worked
Characteristic Description Symbol Unit Formula example
value
Amount of drug
Dose Design parameter 500 mmol
administered.
Time between drug
Dosing interval Design parameter 24 h
dose administrations.
The peak plasma
Cmax concentration of a drug Direct measurement 60.9 mmol/L
after administration.
tmax Time to reach Cmax . Direct measurement 3.9 h

The lowest (trough)

concentration that a
Cmin drug reaches before the Direct measurement 27.7 mmol/L
next dose is
administered.
The apparent volume in
which a drug is
distributed (i.e., the
Volume of
parameter relating drug 6.0 L
distribution
concentration in
plasma to drug amount
in the body).
Amount of drug in a
Concentration given volume of 83.3 mmol/L
plasma.
The time required for
the concentration of the
Absorption drug to double its
1.0 h
half-life original value for oral
and other extravascular
routes.
The rate at which a
Absorption drug enters into the
0.693 −1
rate constant body for oral and other
extravascular routes.
The time required for
Elimination the concentration of the
12 h
half-life drug to reach half of its
original value.
The rate at which a
Elimination
drug is removed from 0.0578 h−1
rate constant
the body.

Rate of infusion
Infusion rate required to balance 50 mmol/h
elimination.

The integral of the

concentration-time
Area under the
curve (after a single 1,320 mmol/L·h
curve
dose or in steady
state).

Clearance The volume of plasma 0.38 L/h

cleared of the drug per
 unit time.
The systemically
Bioavailability available fraction of a Unitless 0.8
drug.

Peak trough fluctuation

Fluctuation within one dosing where 41.8%
interval at steady state.

In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is fairly in dynamic
equilibrium with its elimination. In practice, it is generally considered that steady state is reached when a time
of 3 to 5 times the half-life for a drug after regular dosing is started.

Pharmacokinetic models
Pharmacokinetic modelling is performed
by noncompartmental or compartmental
methods. Noncompartmental methods
estimate the exposure to a drug by
estimating the area under the curve of a
concentration-time graph. Compartmental
methods estimate the concentration-time
graph using kinetic models.
Noncompartmental methods are often
more versatile in that they do not assume
any specific compartmental model and
produce accurate results also acceptable
for bioequivalence studies. The final
outcome of the transformations that a
drug undergoes in an organism and the
rules that determine this fate depend on a The time course of drug plasma concentrations over 96 hours
number of interrelated factors. A number following oral administrations every 24 hours. Note that in steady
of functional models have been state and in linear pharmacokinetics AUCτ=AUC∞.[7] Steady state
developed in order to simplify the study is reached after about 5 × 12 = 60 hours. The graph depicts a
of pharmacokinetics. These models are typical time course of drug plasma concentration and illustrates
based on a consideration of an organism main pharmacokinetic metrics
as a number of related compartments.
The simplest idea is to think of an
organism as only one homogenous compartment. This monocompartmental model presupposes that blood
plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and
that the elimination of the drug is directly proportional to the drug's concentration in the organism (first order
kinetics).

However, these models do not always truly reflect the real situation within an organism. For example, not all
body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in
others with a better blood supply. In addition, there are some tissues (such as the brain tissue) that present a real
barrier to the distribution of drugs, that can be breached with greater or lesser ease depending on the drug's
characteristics. If these relative conditions for the different tissue types are considered along with the rate of
elimination, the organism can be considered to be acting like two compartments: one that we can call the
central compartment that has a more rapid distribution, comprising organs and systems with a well-developed
blood supply; and a peripheral compartment made up of organs with a lower blood flow. Other tissues, such
as the brain, can occupy a variable position depending on a drug's ability to cross the barrier that separates the
organ from the blood supply.

This two compartment model will vary depending on which compartment elimination occurs in. The most
common situation is that elimination occurs in the central compartment as the liver and kidneys are organs with
a good blood supply. However, in some situations it may be that elimination occurs in the peripheral
compartment or even in both. This can mean that there are three possible variations in the two compartment
model, which still do not cover all possibilities.[8]

This model may not be applicable in situations where some of the enzymes responsible for metabolizing the
drug become saturated, or where an active elimination mechanism is present that is independent of the drug's
plasma concentration. In the real world each tissue will have its own distribution characteristics and none of
them will be strictly linear. If we label the drug's volume of distribution within the organism VdF and its
volume of distribution in a tissue VdT the former will be described by an equation that takes into account all
the tissues that act in different ways, that is:

This represents the multi-compartment model with a number of curves that express complicated equations in
order to obtain an overall curve. A number of computer programs have been developed to plot these
equations.[8] However complicated and precise this model may be, it still does not truly represent reality
despite the effort involved in obtaining various distribution values for a drug. This is because the concept of
distribution volume is a relative concept that is not a true reflection of reality. The choice of model therefore
comes down to deciding which one offers the lowest margin of error for the drug involved.

Noncompartmental analysis

Noncompartmental PK analysis is highly dependent on

estimation of total drug exposure. Total drug exposure is most
often estimated by area under the curve (AUC) methods, with the
trapezoidal rule (numerical integration) the most common
method. Due to the dependence on the length of x in the
trapezoidal rule, the area estimation is highly dependent on the
blood/plasma sampling schedule. That is, the closer time points
are, the closer the trapezoids reflect the actual shape of the
concentration-time curve. The number of time points available in
order to perform a successful NCA analysis should be enough to
cover the absorption, distribution and elimination phase to
accurately characterize the drug. Beyond AUC exposure
measures, parameters such as Cmax (maximum concentration),
Tmax(time at maximum concentration), CL and Vd can also be
reported using NCA methods.

Compartmental analysis Graph representing the

monocompartmental action model.
Compartmental PK analysis uses kinetic models to describe and
predict the concentration-time curve. PK compartmental models
are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and
thermodynamics. The advantage of compartmental over some noncompartmental analyses is the ability to
predict the concentration at any time. The disadvantage is the difficulty in developing and validating the proper
model. Compartment-free modelling based on curve stripping does not suffer this limitation. The simplest PK
compartmental model is the one-compartmental PK model with IV bolus administration and first-order
elimination. The most complex PK models (called PBPK models) rely on the use of physiological information
to ease development and validation.

Single-compartment model

Linear pharmacokinetics is so-called because the graph of the relationship between the various factors
involved (dose, blood plasma concentrations, elimination, etc.) gives a straight line or an approximation to one.
For drugs to be effective they need to be able to move rapidly from blood plasma to other body fluids and
tissues.

The change in concentration over time can be expressed as

Multi-compartmental models

The graph for the non-linear relationship between the various factors is
represented by a curve; the relationships between the factors can then be
found by calculating the dimensions of different areas under the curve.
The models used in non-linear pharmacokinetics are largely based on
Michaelis–Menten kinetics. A reaction's factors of non-linearity include
the following:

Multiphasic absorption: Drugs injected intravenously are

removed from the plasma through two primary mechanisms:
(1) Distribution to body tissues and (2) metabolism + excretion
of the drugs. The resulting decrease of the drug's plasma
concentration follows a biphasic pattern (see figure).
Alpha phase: An initial phase of rapid decrease in plasma
concentration. The decrease is primarily attributed to drug
distribution from the central compartment (circulation) into Graphs for absorption and
the peripheral compartments (body tissues). This phase elimination for a non-linear
ends when a pseudo-equilibrium of drug concentration is pharmacokinetic model.
established between the central and peripheral
compartments.
Beta phase: A phase of gradual decrease in plasma concentration after the alpha phase.
The decrease is primarily attributed to drug elimination, that is, metabolism and excretion.[9]
Additional phases (gamma, delta, etc.) are sometimes seen.[10]
A drug's characteristics make a clear distinction between tissues with high and low blood flow.
Enzymatic saturation: When the dose of a drug whose elimination depends on
biotransformation is increased above a certain threshold the enzymes responsible for its
metabolism become saturated. The drug's plasma concentration will then increase
disproportionately and its elimination will no longer be constant.
Induction or enzymatic inhibition: Some drugs have the capacity to inhibit or stimulate their own
metabolism, in negative or positive feedback reactions. As occurs with fluvoxamine, fluoxetine
and phenytoin. As larger doses of these pharmaceuticals are administered the plasma
concentrations of the unmetabolized drug increases and the elimination half-life increases. It is
therefore necessary to adjust the dose or other treatment parameters when a high dosage is
required.
 The kidneys can also establish active elimination
mechanisms for some drugs, independent of plasma
concentrations.

It can therefore be seen that non-linearity can occur because of

reasons that affect the entire pharmacokinetic sequence: absorption,
distribution, metabolism and elimination.

Bioavailability
At a practical level, a drug's bioavailability can be defined as the
proportion of the drug that reaches its site of action. From this
perspective the intravenous administration of a drug provides the
greatest possible bioavailability, and this method is considered to yield Plasma drug concentration vs time
a bioavailability of 1 (or 100%). Bioavailability of other delivery after an IV dose
methods is compared with that of intravenous injection (absolute
bioavailability) or to a standard value related to other
delivery methods in a particular study (relative
bioavailability).

Once a drug's bioavailability has been established it is

possible to calculate the changes that need to be made to
its dosage in order to reach the required blood plasma
Different forms of tablets, which will have different
levels. Bioavailability is, therefore, a mathematical factor
pharmacokinetic behaviours after their
for each individual drug that influences the administered
administration.
dose. It is possible to calculate the amount of a drug in
the blood plasma that has a real potential to bring about
its effect using the formula:

where De is the effective dose, B bioavailability and Da the administered dose.

Therefore, if a drug has a bioavailability of 0.8 (or 80%) and it is administered in a dose of 100 mg, the
equation will demonstrate the following:

De = 0.8 × 100 mg = 80 mg

That is the 100 mg administered represents a blood plasma concentration of 80 mg that has the capacity to
have a pharmaceutical effect.

This concept depends on a series of factors inherent to each drug, such as:[11]

Pharmaceutical form
Chemical form
Route of administration
 Stability
Metabolism

These concepts, which are discussed in detail in their respective titled articles, can be mathematically
quantified and integrated to obtain an overall mathematical equation:

where Q is the drug's purity.[11]

where is the drug's rate of administration and is the rate at which the absorbed drug reaches the
circulatory system.

Finally, using the Henderson-Hasselbalch equation, and knowing the drug's (pH at which there is an
equilibrium between its ionized and non ionized molecules), it is possible to calculate the non ionized
concentration of the drug and therefore the concentration that will be subject to absorption:

When two drugs have the same bioavailability, they are said to be biological equivalents or bioequivalents.
This concept of bioequivalence is important because it is currently used as a yardstick in the authorization of
generic drugs in many countries.

LADME
A number of phases occur once the drug enters into contact with the organism, these are described using the
acronym LADME:

Liberation of the active substance from the delivery system,

Absorption of the active substance by the organism,
Distribution through the blood plasma and different body tissues,
Metabolism that is inactivation of the xenobiotic substance, and finally
Excretion or elimination of the substance or the products of its metabolism.

Some textbooks combine the first two phases as the drug is often administered in an active form, which means
that there is no liberation phase. Others include a phase that combines distribution, metabolism and excretion
into a disposition phase. Other authors include the drug's toxicological aspect in what is known as ADME-Tox
or ADMET.

Each of the phases is subject to physico-chemical interactions between a drug and an organism, which can be
expressed mathematically. Pharmacokinetics is therefore based on mathematical equations that allow the
prediction of a drug's behavior and which place great emphasis on the relationships between drug plasma
concentrations and the time elapsed since the drug's administration.

Analysis
Bioanalytical methods

Bioanalytical methods are necessary to construct a concentration-time profile. Chemical techniques are
employed to measure the concentration of drugs in biological matrix, most often plasma. Proper bioanalytical
methods should be selective and sensitive. For example, microscale thermophoresis can be used to quantify
how the biological matrix/liquid affects the affinity of a drug to its target.[12][13]

Mass spectrometry

Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix (often
plasma or urine) and the need for high sensitivity to observe concentrations after a low dose and a long time
period. The most common instrumentation used in this application is LC-MS with a triple quadrupole mass
spectrometer. Tandem mass spectrometry is usually employed for added specificity. Standard curves and
internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples
represent different time points as a pharmaceutical is administered and then metabolized or cleared from the
body. Blank samples taken before administration are important in determining background and ensuring data
integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve;
however it is common to use curve fitting with more complex functions such as quadratics since the response
of most mass spectrometers is not linear across large concentration ranges.[14][15][16]

There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing
studies, which are seen as a promising alternative to animal experimentation.[17] Recent studies show that
Secondary electrospray ionization (SESI-MS) can be used in drug monitoring, presenting the advantage of
avoiding animal sacrifice.[18]

Population pharmacokinetics
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations
among individuals who are the target patient population receiving clinically relevant doses of a drug of
interest.[19][20][21] Certain patient demographic, pathophysiological, and therapeutical features, such as body
weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-
concentration relationships and can explain variability in exposures. For example, steady-state concentrations
of drugs eliminated mostly by the kidney are usually greater in patients suffering from kidney failure than they
are in patients with normal kidney function receiving the same drug dosage. Population pharmacokinetics
seeks to identify the measurable pathophysiologic factors and explain sources of variability that cause changes
in the dose-concentration relationship and the extent of these changes so that, if such changes are associated
with clinically relevant and significant shifts in exposures that impact the therapeutic index, dosage can be
appropriately modified. An advantage of population pharmacokinetic modelling is its ability to analyse sparse
data sets (sometimes only one concentration measurement per patient is available).

Clinical pharmacokinetics
Clinical pharmacokinetics (arising from the clinical use of population pharmacokinetics) is the direct
application to a therapeutic situation of knowledge regarding a drug's pharmacokinetics and the characteristics
of a population that a patient belongs to (or can be ascribed to).

An example is the relaunch of the use of ciclosporin as an immunosuppressor to facilitate organ transplant. The
drug's therapeutic properties were initially demonstrated, but it was almost never used after it was found to
cause nephrotoxicity in a number of patients.[22] However, it was then realized that it was possible to
individualize a patient's dose of ciclosporin by analysing the patients plasmatic concentrations
 Drugs where pharmacokinetic monitoring is recommended
Antiepileptic Cardioactive Immunosuppressor Antibiotic

medication medication medication medication

Phenytoin
Carbamazepine Ciclosporin
Gentamicin
Valproic acid Tacrolimus
Digoxin Tobramycin
Lamotrigine Sirolimus
Lidocaine Amikacin
Ethosuximide Everolimus
Vancomycin
Phenobarbital Mycophenolate
Primidone

Bronchodilator Cytostatic Antiviral

Coagulation factors
medication medication (HIV) medication

+ Efavirenz Factor VIII,

Methotrexate
Factor IX,
Theophylline 5-Fluorouracil Tenofovir
Factor VIIa,
Irinotecan Ritonavir
Factor XI

(pharmacokinetic monitoring). This practice has allowed this drug to be used again and has facilitated a great
number of organ transplants.

Clinical monitoring is usually carried out by determination of plasma concentrations as this data is usually the
easiest to obtain and the most reliable. The main reasons for determining a drug's plasma concentration
include:[23]

Narrow therapeutic range (difference between toxic and therapeutic concentrations)

High toxicity
High risk to life.

Ecotoxicology
Ecotoxicology is the branch of science that deals with the nature, effects, and interactions of substances that
are harmful to the environment.[24][25]

See also
Blood alcohol Idiosyncratic drug Bioequivalence
concentration reaction Generic drugs
Biological half-life Drug interaction Physiologically based
Bioavailability Patlak plot pharmacokinetic modelling
Enzyme kinetics Pharmacometrics Plateau principle
Pharmacodynamics Pharmacy Toxicokinetics

References
 1. Nordberg M, Duffus J, Templeton DM (1 January 2004). "Glossary of terms used in
toxicokinetics (IUPAC Recommendations 2003)". Pure and Applied Chemistry. 76 (5): 1033–
1082. doi:10.1351/pac200476051033 (https://doi.org/10.1351%2Fpac200476051033).
2. Pharmacokinetics. (2006). In Mosby's Dictionary of Medicine, Nursing & Health Professions.
Philadelphia, PA: Elsevier Health Sciences. Retrieved December 11, 2008, from
http://www.credoreference.com/entry/6686418
3. Knights K, Bryant B (2002). Pharmacology for Health Professionals. Amsterdam: Elsevier.
ISBN 0-7295-3664-5.
4. Koch HP, Ritschel WA (1986). "Liberation". Synopsis der Biopharmazie und Pharmakokinetik
(in German). Landsberg, München: Ecomed. pp. 99–131. ISBN 3-609-64970-4.
5. Ruiz-Garcia A, Bermejo M, Moss A, Casabo VG (February 2008). "Pharmacokinetics in drug
discovery". Journal of Pharmaceutical Sciences. 97 (2): 654–90. doi:10.1002/jps.21009 (https://
doi.org/10.1002%2Fjps.21009). PMID 17630642 (https://pubmed.ncbi.nlm.nih.gov/17630642).
6. AGAH working group PHARMACOKINETICS (2004-02-16). "Collection of terms, symbols,
equations, and explanations of common pharmacokinetic and pharmacodynamic parameters
and some statistical functions" (https://web.archive.org/web/20160508185420/http://www.agah.
eu/fileadmin/_migrated/content_uploads/PK-glossary_PK_working_group_2004.pdf) (PDF).
Arbeitsgemeinschaft für Angewandte Humanpharmakologie (AGAH) (Association for Applied
Human Pharmacology). Archived from the original (http://www.agah.eu/fileadmin/_migrated/con
tent_uploads/PK-glossary_PK_working_group_2004.pdf) (PDF) on 2016-05-08. Retrieved
2011-04-04.
7. Pharmacokinetics Online Resource (https://sepia.unil.ch/pharmacology/index.php?
id=100)University of Lausanne Faculty of Biology and Medicine (FBM)
8. Milo Gibaldi, Donald Perrier. FarmacocinéticaReverté 1982 pages 1–10. ISBN 84-291-5535-X,
9788429155358
9. Gill SC, Moon-Mcdermott L, Hunt TL, Deresinski S, Blaschke T, Sandhaus RA (Sep 1999).
"Phase I Pharmacokinetics of Liposomal Amikacin (MiKasome) in Human Subjects: Dose
Dependence and Urinary Clearance" (http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=1022
44695.html). Abstr Intersci Conf Antimicrob Agents Chemother. 39: 33 (abstract no. 1195).
10. Weiner D, Gabrielsson J (2000). "PK24 – Non-linear kinetics – flow II" (https://books.google.co
m/?id=K-gT2_Ukk0QC&lpg=PA529&dq=pharmacokinetic%20alpha%20beta%20gamma%20p
hase&pg=PA528#v=onepage&q&f=false). Pharmacokinetic/pharmacodynamic data analysis:
concepts and applications. Apotekarsocieteten. pp. 527–36. ISBN 91-86274-92-9.
11. Michael E. Winter, Mary Anne Koda-Kimple, Lloyd Y. Young, Emilio Pol Yanguas
Farmacocinética clínica básica Ediciones Díaz de Santos, 1994 pgs. 8–14 ISBN 84-7978-147-
5, 9788479781477 (in Spanish)
12. Baaske P, Wienken CJ, Reineck P, Duhr S, Braun D (March 2010). "Optical thermophoresis for
quantifying the buffer dependence of aptamer binding". Angewandte Chemie. 49 (12): 2238–
41. doi:10.1002/anie.200903998 (https://doi.org/10.1002%2Fanie.200903998).
PMID 20186894 (https://pubmed.ncbi.nlm.nih.gov/20186894). Lay summary (http://www.physor
g.com/news186225693.html) – Phsyorg.com.
13. Wienken CJ, Baaske P, Rothbauer U, Braun D, Duhr S (October 2010). "Protein-binding
assays in biological liquids using microscale thermophoresis" (https://doi.org/10.1038/ncomms
1093). Nature Communications. 1 (7): 100. Bibcode:2010NatCo...1..100W (https://ui.adsabs.har
vard.edu/abs/2010NatCo...1..100W). doi:10.1038/ncomms1093 (https://doi.org/10.1038%2Fnco
mms1093). PMID 20981028 (https://pubmed.ncbi.nlm.nih.gov/20981028).
14. Hsieh Y, Korfmacher WA (June 2006). "Increasing speed and throughput when using HPLC-
MS/MS systems for drug metabolism and pharmacokinetic screening". Current Drug
Metabolism. 7 (5): 479–89. doi:10.2174/138920006777697963 (https://doi.org/10.2174%2F138
920006777697963). PMID 16787157 (https://pubmed.ncbi.nlm.nih.gov/16787157).
15. Covey TR, Lee ED, Henion JD (October 1986). "High-speed liquid chromatography/tandem
mass spectrometry for the determination of drugs in biological samples". Analytical Chemistry.
58 (12): 2453–60. doi:10.1021/ac00125a022 (https://doi.org/10.1021%2Fac00125a022).
PMID 3789400 (https://pubmed.ncbi.nlm.nih.gov/3789400).
16. Covey TR, Crowther JB, Dewey EA, Henion JD (February 1985). "Thermospray liquid
chromatography/mass spectrometry determination of drugs and their metabolites in biological
fluids". Analytical Chemistry. 57 (2): 474–81. doi:10.1021/ac50001a036 (https://doi.org/10.102
1%2Fac50001a036). PMID 3977076 (https://pubmed.ncbi.nlm.nih.gov/3977076).
17. Committee for Medicinal Products for Human Use (CHMP) (December 2009). "ICH guideline
M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing
authorisation for pharmaceuticals" (http://www.ema.europa.eu/docs/en_GB/document_library/S
cientific_guideline/2009/09/WC500002720.pdf) (PDF). European Medicines Agency,
Evaluation of Medicines for Human Use. EMA/CPMP/ICH/286/1995. Retrieved 4 May 2013.
18. Li, Xue; Martinez-Lozano Sinues, Pablo; Dallmann, Robert; Bregy, Lukas; Hollmén, Maija;
Proulx, Steven; Brown, Steven A.; Detmar, Michael; Kohler, Malcolm; Zenobi, Renato (2015-06-
26). "Drug Pharmacokinetics Determined by Real-Time Analysis of Mouse Breath".
Angewandte Chemie International Edition. 54 (27): 7815–7818. doi:10.1002/anie.201503312
(https://doi.org/10.1002%2Fanie.201503312). hdl:20.500.11850/102558 (https://hdl.handle.net/
20.500.11850%2F102558). PMID 26015026 (https://pubmed.ncbi.nlm.nih.gov/26015026).
19. Sheiner LB, Rosenberg B, Marathe VV (October 1977). "Estimation of population
characteristics of pharmacokinetic parameters from routine clinical data". Journal of
Pharmacokinetics and Biopharmaceutics. 5 (5): 445–79. doi:10.1007/BF01061728 (https://doi.o
rg/10.1007%2FBF01061728). PMID 925881 (https://pubmed.ncbi.nlm.nih.gov/925881).
20. Sheiner LB, Beal S, Rosenberg B, Marathe VV (September 1979). "Forecasting individual
pharmacokinetics". Clinical Pharmacology and Therapeutics. 26 (3): 294–305.
doi:10.1002/cpt1979263294 (https://doi.org/10.1002%2Fcpt1979263294). PMID 466923 (http
s://pubmed.ncbi.nlm.nih.gov/466923).
21. Bonate PL (October 2005). "Recommended reading in population pharmacokinetic
pharmacodynamics" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750974). The AAPS
Journal. 7 (2): E363–73. doi:10.1208/aapsj070237 (https://doi.org/10.1208%2Faapsj070237).
PMC 2750974 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750974). PMID 16353916 (http
s://pubmed.ncbi.nlm.nih.gov/16353916).
22. O'Valle, F.; García del Moral, R.; Andujar, M. (1995). "Mecanismos de nefrotoxicidad por
ciclosporina A a nivel celular" (http://www.revistanefrologia.com/es-publicacion-nefrologia-artic
ulo-mecanismos-nefrotoxicidad-por-ciclosporina-a-nivel-celular-X0211699595022690).
Nefrologia (in Spanish). 15 Supplement 1.
23. Joaquín Herrera Carranza Manual de farmacia clínica y Atención Farmacéutica (https://books.g
oogle.com/books?id=7Vw7a4wBzRgC) (in Spanish). Published by Elsevier España, 2003;
page 159. ISBN 84-8174-658-4
24. Jager T, Albert C, Preuss TG, Ashauer R (April 2011). "General unified threshold model of
survival--a toxicokinetic-toxicodynamic framework for ecotoxicology". Environmental Science &
Technology. 45 (7): 2529–40. Bibcode:2011EnST...45.2529J (https://ui.adsabs.harvard.edu/ab
s/2011EnST...45.2529J). doi:10.1021/es103092a (https://doi.org/10.1021%2Fes103092a).
PMID 21366215 (https://pubmed.ncbi.nlm.nih.gov/21366215).
25. Ashauer R. "Toxicokinetic-Toxicodynamic Models – Ecotoxicology and Models" (https://web.arc
hive.org/web/20120405200941/http://www.ecotoxmodels.org/research-publications-projects/tox
icokinetic-toxicodynamic-models/). Swiss Federal Institute of Aquatic Science and Technology.
Archived from the original (http://www.ecotoxmodels.org/research-publications-projects/toxicoki
netic-toxicodynamic-models/) on 2012-04-05. Retrieved 2011-12-03.

External links
Software
Noncompartmental

Freeware: bear (http://pkpd.kmu.edu.tw/bear/) and PK (http://cran.at.r-project.org/web/package

s/PK/index.html) for R
Commercial: MLAB, EquivTest (http://www.statistical-solutions-software.com/products-page/eq
uivtest-for-equivalence-testing/), Kinetica (http://www.thermoscientific.com/ecomm/servlet/produ
ctsdetail?productId=11962424), MATLAB/SimBiology (http://www.mathworks.com/products/sim
biology/), PKMP (http://aplanalyst.com/),Phoenix/WinNonlin (https://web.archive.org/web/20130
210014412/http://www.certara.com/products/pkpd/phx-wnl), PK Solutions (https://web.archive.o
rg/web/20110719235952/http://www.summitpk.com/pksolutions/pksolutions.htm), RapidNCA (h
ttps://web.archive.org/web/20150407143248/http://www.mango-solutions.com/wp/products-ser
vices/products/rapidnca/).

Compartment based

Freeware: ADAPT (http://bmsr.usc.edu/software/adapt/), Boomer (http://www.boomer.org/) (GUI

(http://pkpd.kmu.edu.tw/jguib/)), SBPKPD.org (Systems Biology Driven Pharmacokinetics and
Pharmacodynamics) (http://www.sbpkpd.org/), WinSAAM (https://web.archive.org/web/2011031
3141127/http://www.winsaam.com/), PKfit (http://cran.csie.ntu.edu.tw/web/packages/PKfit/inde
x.html) for R, PharmaCalc and PharmaCalcCL (http://www.biopharmacy.ethz.ch/), Java
applications.
Commercial: Imalytics (http://www.imalytics.philips.com/products/pharmacokinetic-modeling/ph
armacokinetic-modeling.page), Kinetica, MATLAB/SimBiology (http://www.mathworks.com/pro
ducts/simbiology/), Phoenix/WinNonlin (https://web.archive.org/web/20130210014412/http://w
ww.certara.com/products/pkpd/phx-wnl), PK Solutions, PottersWheel, ProcessDB (http://www.i
ntegrativebioinformatics.com/processdb.html), SAAM II (http://depts.washington.edu/saam2/).

Physiologically based

Freeware: MCSim (https://www.gnu.org/software/mcsim/)

Commercial: acslX (https://web.archive.org/web/20160109094324/http://acslx.com/), Cloe PK
(http://www.cloegateway.com/), GastroPlus (http://www.simulations-plus.com/Products.aspx?gr
pID=3&cID=16&pID=11), MATLAB/SimBiology (http://www.mathworks.com/products/simbiolog
y/), PK-Sim (http://www.systems-biology.com/products/pk-sim.html), ProcessDB (http://www.inte
grativebioinformatics.com/processdb.html), Simcyp (http://www.simcyp.com/), Entelos
PhysioLab (https://web.archive.org/web/20080704113719/http://entelos.com/)
Phoenix/WinNonlin (https://web.archive.org/web/20130210014412/http://www.certara.com/prod
ucts/pkpd/phx-wnl), ADME Workbench (https://web.archive.org/web/20140221231528/http://ww
w.admewb.com/).

Population PK

Freeware: WinBUGS, ADAPT, S-ADAPT / SADAPT-TRAN, Boomer, PKBugs (https://web.archi

ve.org/web/20060716224622/http://www.winbugs-development.org.uk/pkbugs/home.html),
Pmetrics (http://www.lapk.org/pmetrics.php) for R.
Commercial: Kinetica, MATLAB/SimBiology (http://www.mathworks.com/products/simbiology/),
Monolix (http://lixoft.com/products/monolix/), NONMEM, Phoenix/NLME (https://web.archive.or
g/web/20110201042414/http://www.pharsight.com/products/prod_phoenix_nlme_home.php),
PopKinetics (http://depts.washington.edu/saam2/popKinetics/index.html) for SAAM II,
USC*PACK (http://www.lapk.org/software.php), DoseMe-Rx (https://doseme-rx.com), Navigator
Workbench (https://web.archive.org/web/20150408064739/http://www.mango-solutions.com/w
p/products-services/products/navigator/).
Simulation

All model based software above.

Freeware: COPASI, Berkeley Madonna, MEGen (http://xnet.hsl.gov.uk/megen/).

Educational centres

Global centres with the highest profiles for providing in-depth training include the Universities of Buffalo,
Florida, Gothenburg, Leiden, Otago, San Francisco, Beijing, Tokyo, Uppsala, Washington, Manchester,
Monash University, and University of Sheffield.[1]

1. Tucker GT (June 2012). "Research priorities in pharmacokinetics" (https://www.ncbi.nlm.nih.go

v/pmc/articles/PMC3391520). British Journal of Clinical Pharmacology. 73 (6): 924–6.
doi:10.1111/j.1365-2125.2012.04238.x (https://doi.org/10.1111%2Fj.1365-2125.2012.04238.x).
PMC 3391520 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391520). PMID 22360418 (http
s://pubmed.ncbi.nlm.nih.gov/22360418).

Retrieved from "https://en.wikipedia.org/w/index.php?title=Pharmacokinetics&oldid=971405641"

This page was last edited on 5 August 2020, at 23:09 (UTC).

Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this
site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia
Foundation, Inc., a non-profit organization.