Pharmacokinetics

(药物代谢动力学)

朱玲 [email protected] 四川大学华西 药理
 Pharmacokinetics
Drug Administration
Absorption
Drug
Drug in Concentration Drug
Tissues of in Systemic Metabolism or
Distribution Circulation Excreted

Distribution Elimination
Drug Concentration
at Site of Action

Pharmacodynamics
Pharmacologic Effect

Clinical Response

Adverse reaction Efficacy

 Why do I need to know PK?
Optimize drug therapy to obtain a
predictable response!

(1) Drug of choice

(2) How much
(3) How often
(4) For how long
 Pharmacokinetics
药物体内处置
(Disposition) Time-dependent
change of
吸收 (Absorption) plasma drug
分布 (Distribution) concentration
and total amount
代谢 (Metabolism) of drug in the
排泄 (Excretion) body
 Contents
⚫ Movement of drug molecular across cell member:
Influence of pH…….

⚫ Drug absorption, Distribution, metabolism and

excretion : First pass elimination, Plasma protein binding, Cytochrome
p450(CYP450)……

⚫ Time-dependent change of plasma drug concentration

and total amount of drug in the body, Kinetic process ,
Important pharmacokinetic parameters: First order
elimination kinetics, Zero order elimination kinetics,, T1/2 (half life ),
Bioavailability, The volume of distribution (V) , Css, CL……
 Section 1
Intracorporal process
体内过程
Part1 Transportation of drugs across membranes
Review
Cytosis

如
何
转
运

(Diffusion through the cell membrane 药物转运方式模式图

lipid (The most important way)
2、Transmembrane transport rule
 Cell membrane permeability, area, thickness
面积×通透系数
OATP, OCT, PEPT,
 Blood flow 通透量（单位时间） =（C1-C2）×
P-glycoprotein, MRP
厚度
 The amount and function of cell membrane transport
proteins Lipid solubility and
water solubility.
 Concentration difference Oil/water partition
coefficient of the drug
 Solubility and dissociation of drugs
Degree of
Lipid solubility
ionization and pH
→Transmembrane
of body fluids
ABC (ATP binding cassette) and SLC (solute carrier) transporters.
Drug competition, inhibition and induction of transporters
is one of the mechanisms of drug interaction.
 Properties of Ionizable Drugs
➢Many drugs are either weak acids or bases, which
complicates penetration of membranes.
•C8H7O2COOH < => C8H7O2COO- + H+ •C12H11CIN3NH3+ <= > C12H11CIN3NH2 + H+
•neutral aspirin (C8H7O2COOH) in •pyrimethamine cation (C12H11CIN3NH3+) in
equilibrium with aspirin anion equilibrium with neutral pyrimethamine
(C8H7O2COO- ) and a proton (H+ ) (C12H11CIN3NH2) and a proton (H+ )

➢They are more water soluble when ionized (hydrophilic).

➢Ionized drugs pass lipid membranes very poorly.
➢They are more lipid soluble when unionized (hydrophobic).
 Ionization state of the drug
➢ Ionization state of the drug is an important factor: charged
drugs diffuse-through lipid environments with difficulty.

➢ pH and the drug pKa,

important in
determining the
ionization state, will
influence significantly
transport. Depending
on the pH of the
environment these
drugs can be ionized or
unionized. 离子障ion trapping
 Lipid Membrane

Handerson-Hasselbach formula ： HA  H+ + A-

BH+  B + H+

For weak acid drug For weak basic drug

HA H+ + A- BH+ H+ + B
Ka = [ H + ] [A- ] Ka = [ H +] [ B ]
[ HA ] [ BH+ ]

-lgKa=-lg[H+]-lg [A-] [B]

-lgKa =- lg[H+] -lg
[HA] [BH+]
The negative logarithm of the
dissociation constant：pKa
 pka = pH - lg [A-] pka = pH - lg [B]
[ HA ] [ BH+ ]

pH - pka = lg [ A- ] pka - pH = lg [ BH+ ]

[ HA ] [B]

10 pH -pka = [ A- ] 10 pka -pH = [ BH+ ]

[ HA ] [B]

pH = pka pH = pka
[ HA ] = [ A- ] [ B ] = [ BH +]

pKa=pH when unionized and ionized forms are equal

pka : the pH when 50% drug ionized
Ionization Versus pH
weak acid weak base
pH -pka ionized pH -pka ionized
Base (B) -3 0.1% -3 99.9%
-2 1% -2 99%
-1 10% -1 90%
0 50% 0 50%
1 90% 1 10%
2 99% 2 1%
3 99.9% 3 0.1%
Summary

Moral of the story...

Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from basic environments

So...
To  absorption of an acidic drug…acidify the environment
To  absorption (elimination) of an acidic drug
……alkalanize the environment...
A lipid membrane structures
weak acid at acid pH will be more lipid-soluble because it is uncharged and
uncharged molecules move more readily through a lipid (nonpolar) environment,
like the some membrane, than charged molecules
A weak base at alkaline pH will be more lipid-soluble because at alkaline pH a
proton will dissociate from molecule leaving it uncharged and again free to
move through
Weak acids pKa weak bases pKa
•phenobarbital
7.4 •cocaine 8.5
(Luminal)
•pentobarbital
8.1 •ephedrine 8.7
(Nembutal)
•chlordiazepoxide
•acetaminophen 9.5 4.6
(Librium)
•aspirin 3.5 •morphine 7.9
•furosemide 3.9 •diazepam 3.3
Part2 Process of drugs in the body
1. Drug absorption
• Absorption is the transfer of a drug from
its administration site to the blood stream.
• The rate and efficiency of absorption
depend on the route of administration.
 Factors Affecting
Gastrointestinal (GI) Absorption
Medicines factors
➢ Route of administration
 Most convenient,
Routes of Administration
most economical
Enteral: Oral (p.o.) Parenteral: Injection
pertectum Intravenous (i.v)
Fastast
Respiratory intravenously guttae
Inhalation (iv gtt)
Intranasal Subcutaneous (s.c)
Intratracheal
Intramuscular (i.m)
Topical Application
Intraperitoneal (i.p)
Mucous membrane
Rectal or sublingual
transdermal
 Factors Affecting
Gastrointestinal (GI) Absorption
Medicines factors
➢ Route of administration
◼ The more lipid soluble (less polar) a drug is, the better it is
absorbed from the gut
◼ Ionization state : Weak acids are absorbed best from the
stomach while weak bases from the intestine.
◼ Molecule: small molecules are easily absorbed
Drug itself: molecular weight, fat solubility, etc
Drug forms: tablets, capsules, dispersible tablets, liquid, aerosol particle
size, etc
 Factors Affecting
Gastrointestinal (GI) Absorption
Physiological Factors
◼ pH
Stomach: about1.5-2 .5 Absorption area of Gastrointestinal(m2)
mouth 0.5-l .0
Intestine: about7.5-8 per rectum 0.02
Stomach 0.1-0.2
◼ Contact time and surface area 小Intestine 100
大Intestine 0.04-0.07
◼ Blood flow
胃酸 蠕动度
The duodenum （small stomach Acid motility
稀释
intestine）is the major dilution

site of absorption. 微生物群

microflora
消化酶
◼First pass eliminaiton digestive enzymes
 首过消除(First pass eliminaiton, first
pass metabolism, first pass effect)
enter into
intestinal
Portal vein
systematic
wall blood

metabolite
metabolite
Feces excretion

吸收过程是药物从用药部位进入体内血循环
 First-Pass Effect
◼ Drugs are absorbed from the GI and pass through the liver
before enter into systematic blood
◼ Elimination may occur in the intestinal wall and in liver
(metabolite and excrete)
◼ Result in bioavailability reduction
◼ Drugs with large first pass effect exhibit significant differences
in pharmacological effects comparing oral vs. IV
administration
Avoid provision:
sublingual administration,
rectal administration,
transdermal administration
inhalation………
 2. Drug Distribution
Drug Distribution is the process by which a drug
reversibly leaves the blood stream and enters the
interstitium (extracellular fluid) and / or the cells of
the tissue.

血浆蛋白
 Drug Distribution
Important Affecting Factors
◼ Blood flow
◼ Capillary permeability : The ability of a drug to reach
various tissues will depend on the permeability of the capillaries
at the site in question.
◼ pH
◼ Tissue affinity Special barrier
◼ Lipid solubility : Lipid solubility will affect the ability of the
drug to bind to plasma proteins and to cross membrane
Redistribution
◼ Plasma and tissue protein binding
Special barrier Blood-Brain Barrier
Endothelial cells Pinocytosis of
The blood brain barrier consists of compounds
<~25,000 daltons
cell tightly packed around the
capillaries of the CNS. What Solutes move
through
fenestrations by
characteristics must a drug possess passive diffusion
Nonbrain capillary
to easily cross this barrier? Endothelia cells

Solutes must
diffuse through
Non-protein bound, non-ionized, Ion pumps two
membranes
Why?
and highly lipid soluble +
(Na , k -
ATPase)
+

Brain capillary
Special barrier
◼ Blood-brain barrier
Except when a drug has a specific uptake
mechanism, only small, lipid-soluble drugs are
able to enter the CNS.
Carrier transport, such as glucose
Inflammation of the epithelial layer may increase
its permeability.

敏感菌脑膜炎时，
青霉素
大剂量青霉素有效
Special barrier
◼ Placenta barrier: The placenta is not an effective
barrier to most drugs.

◼ Blood-eye barrier

其他：病理性变化，如肺结核空洞
 Drug Distribution
➢Redistribution

心 肝 脑 脂肪

A highly lipophilic-drug may:

➢rapidly partition into the brain
➢act briefly
➢and then redistribute into other tissues -- often ultimately
concentrating in adipose tissue.
➢Redistribution is the mechanism responsible for termination of
action of thiopental (pentothal),an anesthetic inducing agent.
 白蛋白—弱酸药物
Plasma protein binding α1酸性糖蛋白—弱碱药物
脂蛋白—脂溶性强药物
Many drugs are bound to plasma proteins--- albumin, α1-acid glycol-protein
and lipoprotein
 The binding is reversible and there is a dynamic equilibrium between the
bound and unbound forms of a drug.
D D + P DP
• Bound drug is not effective , can’t across the
plasma membrane, and serve as a substantial
drug reservoir
• Binding form is saturable
• Binding form is relatively nonselective(competition)
Rate of binding: binging form / total form

Extensive protein binding slows drug elimination

 Drugs with high binding rates may compete with the same
protein and undergo replacement, resulting in blood
concentrations of free drugs↑, and toxicity↑.
warfarin +butazodine bleeding

Neonatal
+sulfonamide kernicterus
s Replace
Nuclear jaundice
bilirubin
Hypoalbuminemia or
Easy to poisoning
deterioration in plasma
Protein binding ratio ↓
Bound Free Drug 98% 2%
Alone 99% 1% combination 96% 4%
 3. Drug Metabolism
◼ Drug metabolism or biotransformation refers to the process
of modifying or altering the chemical composition of the
drug.
◼ Most drug metabolism occurs in the liver
 Drug Metabolism
(1) the purpose of biotransformation
◼ The drug (most) from activity to less activity or
inactivity Inactivation pro-drug
◼ The drug (less) from inactivity to activity activation
Sometimes metabolites retain biological activity and may be toxic.
◼ The important pathway of excretion of drug.
◼ Biotransformation reactions produces more polar,
hydrophilic, biologically inactive molecules -- that are more
readily excreted.
 （2）Metabolism proceeds in two phases
Phase I and Phase II Reactions
Oxidation
Oxidation Glucuronidation
Reduction Acetylation
Hydroxylation
Dealkylation Absorption
Hydrolysis Metabolism Elimination Gluathione conjugate
Sulfate conjugate
Deamination
Methylation
Phase I Phase II

Drug Conjugation

Modified activity Conjugation

Drug
No activity
Conjugation
Modified activity

Drug
No activity
Drug
Lipophilic Hydrophilic
 Drug metabolizing enzymes

phase Ⅰ phase Ⅱ

metabolites
① Nonmicrosomal enzymes: AChE COMT MAO
② Microsomal enzymes
 Drug metabolizing enzymes

phase Ⅰ phase Ⅱ
Microsomal enzymes
Hepatic drug metabolizing enzymes metabolites
Cytochrome 450 System（CYP450）
含黄素单氧化酶 flavin-containing monooxygenases FMO
环氧化物水解酶 epoxide hydrolases EH
结合酶系 conjugating enzymes CE
脱氢酶系 dehydrogenases DH
 located in lipophilic, hepatic
endoplasmic reticulum membranes:
smooth endoplasmic reticulum
(Cytochrome P450 )

Location of CYPs in the cell.

Characteristics
➢Non-selective
➢Individual variation
➢Capacity Limitation Cytochrome P450 cycle in drug oxidations. e–,
➢Competitive and Inducible electron; RH, parent drug; ROH, oxidized metabolite.
 Individual Differences in Drug Metabolism

• Age: Elderly have lower content of CYP

enzymes and thus slower drug
metabolism
(Remember: In the elderly “Lower the dose”)
Infants at birth lack conjugating enzyme
(UDPGT) and thus have limited capacity to
eliminate Phase I metabolites of drugs
• Genetics: Polymorphism of drug
metabolizing enzymes
• Environment: Presence of other drugs,
exposure to chemicals in the workplace,
foods etc can induce or inhibit enzymes
The hepatic microsomal enzymes inducers (肝药酶诱导剂) :
◼ The drugs that can increase synthesis and activity of the hepatic
microsomal enzymes.
◼ It leads to an increased rate of biotransformation and corresponding
decreases in the availability of the parent drug.

The hepatic microsomal enzymes inhibitors (肝药酶抑制剂):

◼ The drugs that can decrease synthesis and activity of the hepatic
microsomal enzymes.
◼ Inhibition of drug biotransformation enzymes results in elevated levels
of the parent drug, prolonged pharmacological effects, and an
increased incidence of drug-induced toxicity.
 CYP P450
Contributions to Drug Metabolism
5 CYP enzymes account for ~95% of CYP P-450 drug metabolism

(from Guengerich, 2003)

 Drug Metabolism: Summary
➢ Phase I (functionalization), Phase II (conjugation)
➢ CYPs are most important Phase I enzymes
➢ Metabolites are often pharmacologically inactive, others are
pharmacologically active
➢ Individual differences in enzymes due to environment and genetics
(polymorphisms) can result in altered pharmacokinetics
➢ Exposure to drugs can result in CYP inhibition or CYP induction that
will result in changes in the dose-response profile
➢ Drug-drug interactions are likely to occur when the individual takes
multiple drugs, increasing the potential for adverse reactions
When prescribing a medication, always ask yourself
- what is the potential for P450 related issues
- what is the potential for drug-drug interactions
 4 Excretion (排泄)
Transport of drug prototypes or metabolites
by excreting or secreting organs

Routes Kidney（ the most important ）

 Bile, intestine
 Lung Perspiration,
 Skin (Sweat glands)
 Saliva
 Breast Milk
 tears etc……
 4. Drug excretion
Affecting factor
• Presence of kidney disease. eg. renal failure.
• Altered renal blood flow.
• pH of urine.
• Concentration of the drug in plasma.
• Molecular weight of the drug.
◼ Drug competitive
pH of urine is the most important factor

Acid urine Basic urine

Acid Non-ionized ↑ Non-ionized ↓
drug re-absorption ↑ re-absorption ↓
Excretion ↓ excretion ↑
Basic Non-ionized ↓ Non-ionized ↑
drug re-absorption ↓ re-absorption ↑
excretion ↑ excretion ↓
 胆汁排泄
(biliary excretion) Liver
和
肝肠循环 Bile duct
(Enterohepatic
recycling)

Gut
Portal vein
hepato-enteral circulation (肝肠循环)：Drugs and
metabolites are secreted by the liver into bile.
These then enter the duodenum and the small
intestine. Some drugs will be reabsorbed back Feces
into the bloodstream and return to the liver. excretion
 Biliary excretion
Active passport
⚫ P-糖蛋白（p-glycoprotein）
⚫ 多药耐药相关蛋白２（multidrug
resistance-associated protein-type2，
MRP2）

Dubin-Johnson
MRP2
 Termination of drug effects

 Usually by:
 biotransformation (metabolism)
 excretion
 Drug effects may also be terminated by
redistribution -- from its site of action to other
tissues or sites
CONCLUSION
Intracorporal process

Once the drug is absorbed, the

four basic processes of ADME
continue and occur distribution
simultaneously, which are factors
that determine the rise and fall of
blood drug concentration

excretion
Q&A

THANK YOU