Transcript 没有幻灯片标题

Chapter 1
Pharmacokinetics
药物代谢动力学
 PK process in the body
 Kinetic processes
Part A Pharmacokinetic Processes
 1. Overview
 2. Transport of Drug in the Body
 3. Pharmacokinetic Processes of the Drug

in the Body
Overview
A. aqueous
B. lipid cell
channels in the membranes
intercellular
junctions
C. carriers
(transporters)
(into or out of
cells)
D. endocytosis
exocytosis
Mechanisms of drug permeation
Part A Pharmacokinetic Processes
 2. Transport of Drug in the Body
 2.1 Transmembrane Transport of Drugs
 (1) Non-carrier transport


Simple diffusion（简单扩散/单纯扩散）
Filtration（滤过）
Part A Pharmacokinetic
Processes
Characteristics of simple diffusion
Not involving specific carriers
Energy-independent
No saturability
No competition with other drugs
Concentration gradient (down-hill)
Part A Pharmacokinetic Processes
 (2) Carrier-mediated transport







a. Active transport
Characteristics of active transport
Involving specific carrier (transporter)
Energy-dependent
Saturability
Competition at same carrier
Moving against concentration gradient (up-hill)
Part A Pharmacokinetic Processes
 b. Facilitated diffusion（易化扩散）

(transporter-mediated diffusion)





Involving specific carriers (transporter)
Energy-independent
Saturability
Competition with other drugs
Concentration gradient (down-hill)
 (3) Membrane moving transport（膜动转运）

Endocytosis/exocytosis（入胞/出胞）
Part A Pharmacokinetic Processes
 A. Simple diffusion
Most drugs are weak
acids or bases.
Their diffusion
passing through cell
membrane depends
the lipid-soluble state
(un-ionized form)
Part A Pharmacokinetic Processes
 Determinants of simple diffusion

For most drugs of small molecules (usually
are weak acids or weak bases):

Lipid-soluble or un-ionized forms

pKa of the drug and pH of the body fluid

The pKa is the pH at which the concentrations of
the ionized and un-ionized forms are equal.
Part A Pharmacokinetic Processes
 Henderson-Hasselbalch equation
 Weak acid drugs:
 pH - pKa = log ( [A-] / [HA] )
 pKa - pH = log ( [HA] / [A-] )
 Weak base drugs:
 pKa - pH = log ( [BH+] / [B] )
 pH - pKa = log ( [B] / [BH+] )
Part A Pharmacokinetic Processes
pH
pKa
Weak
acids
And / or
Weak
bases
And / or
And / or
And / or
un-ionized
form
lipidsoluble
Simple
diffusion
Part A Pharmacokinetic Processes
 Implications

Absorption: Stomach/intestine

Distribution: Plasma/intracellular

Excretion: Urine pH/weak acid or base
Weak acid
Weak base
Trapping of a weak base (methamphetamine) in the
urine when the urine is more acidic than the blood
B. Carrier (transporter)-mediated
transport
Three types of functional membrane proteins.
Models of transmembrane transport across the lipid bilayer
 Transporter superfamily（转运体超家族）
 根据不断增加的转运体成员，人类基因命名委员会对转运体作了标准化命
名，分为两大类：
 ATP-结合盒转运体（ATP-binding cassette [ABC]
transporters）— mediating active transport



12次跨膜结构 （P-gp、MRP4、MRP5）
17次跨膜结构 （MRP1、MRP2、MRP3、MRP6）
6次跨膜结构 （BCRP, 组成二聚体发挥作用）
 溶质载体转运体（solute carrier [SLC] transporters） —
mediating facilitated diffusion




有机阴离子转运体（organic anion transporter, OAT）家族
有机阳离子转运体（organic cation transporter, OCT）家族
多肽转运体（peptide transporter, PEPT）
核苷转运体（nucleoside transporter, NT）
Primary active transport
(P-glycoprotein, multidrug
resistance protein [MRP] )
Secondary active
transport
+
facilitated diffusion
(organic anion /
caion transporters)
Transporters of drugs in PK processes
Part A Pharmacokinetic Processes
 2.2 Free and Bound Forms

Plasma protein binding

Tissue / organ affinity
Part A Pharmacokinetic Processes
 3. Fate of the drug in the body






Absorption
Distribution
Metabolism
(Biotransformation)
Excretion
－ ADME
ADME
Part A Pharmacokinetic Processes
 3.1 Absorption
 Absorption is the transfer of a drug from its site of
administration to the blood stream.




Gastrointestinal tract
Parenteral injection - i.m., s.c.
Inhalation
Transdermal
Part A Pharmacokinetic Processes
 (1) Gastrointestinal tract
 Route:



Oral
Sublingual
Rectal
 Absorption sites:




Oral
Gastric
Intestinal
Rectal
Part A Pharmacokinetic Processes
 Factors influencing absorption:





blood flow to the absorption site
total surface area available for absorption
contact time at the absorption surface
physic-chemical properties of the drug
first-pass elimination
Part A Pharmacokinetic Processes
 First-pass elimination（首过消除）
 When a drug is absorbed across
the GI tract, it enters the portal
circulation before entering the
systemic circulation. If the drug is
rapidly metabolized by the liver or
intestinal mucosa, the amount of
unchanged drug that gains access
to the systemic circulation is
decreased.
Part A Pharmacokinetic Processes
 (2) Parenteral injection


intramuscular injection ( i.m. )
subcutaneous injection ( s.c. )



Determinants
Local blood flow
Solubility of the drug
Part A Pharmacokinetic Processes
 (3) Others
 Inhalation
 Transdermal
 Intranasal
 Topical
Part A Pharmacokinetic Processes
 3.2 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 tissues.



Blood flow-dependent phase of distribution
Selective distribution
Tissue-plasma balance: importance of measuring
plasma concentration
Body fluid
volume:
Sites of drug
distribution
Part A Pharmacokinetic Processes
 (1) Binding of drug to plasma proteins





Bound drug:
can not distribute / inactive temporally
reversible (storage form)/ percentage of binding
plasma protein capacity
competitive displacement
Part A Pharmacokinetic Processes
 Competitive displacement
 Class I drugs: Dose less than available binding sites.
Most drug molecules are bound to the proteins and free
drug concentration is low.
 Class II drugs:
Dose greater than available binding
sites. Most proteins contain a bound drug and free drug
concentration is significant.
 Class I + Class II drugs: Displacement of Class I
drug occurs when a Class II drug is administered
simultaneously.
Example:
Class I: Tolbutamide (甲苯磺丁脲)
Class II: Sulfonamide (磺胺类药物)
competitive displacement
Part A Pharmacokinetic Processes
(2) Physic-chemical properties of the drug
(3) Blood flow and re-distribution
(4) Affinity to organs or tissues
(5) Barriers
Blood-brain barrier (BBB)
Placental barrier
Blood-eye barrier
Blood-brain barrier (BBB)
Able to pass through
Unable to pass through
Small molecules
Large molecules
Lipid-soluble
Water-soluble
Transporter-mediation
Part A Pharmacokinetic Processes
Amount of drug passing through bloodbrain barrier
Percentage of drug in c.s.f.
Increases when
Inflammation
Larger doses used
BBB permeability
increases in
inflammation
Placental barrier:
More permeable
Drugs for pregnant
women:
A, B – relatively safe
C - caution
D, X - toxic
Part A Pharmacokinetic Processes
 3.3 Metabolism (biotransformation)
 Drug metabolism is the process transforming lipophilic drug
into more hydrophilic metabolites, which is essential for the
elimination of these compounds from the body and termination
of their biological activity.
 (1) Metabolism sites


Liver: for most of the drugs
Other organs/tissues: intestine, kidney, lung,
plasma, etc.
Part A Pharmacokinetic Processes
 (2) Phases of metabolism



Phase I: Oxidation, reduction,
most drugs are inactivated
few (prodrugs) is activated

Phase II: Conjugation

inactivated


hydrolysis
Metabolites: more water-soluble
easier to excrete
Part A Pharmacokinetic Processes
Part A Pharmacokinetic Processes
 (3) Enzymes in drug metabolism



Enzymes in Phase I:
cytochrome-P450
many other enzymes




Enzymes in Phase II:
acetylase
glucuronosyltransferase
etc.
Superfamily of cytochrome-P450
CYP2A6（cytochrome-P450 / family / subfamily / member）
Part A Pharmacokinetic Processes
 (4) Properties of drug metabolism
enzymes
 a. Lower selectivity to substrates
 b. Larger individual variability
 c. Induction and inhibition
determinants (including drugs)
by
environmental
Rapid acetylation
Slow acetylation
Individual variability of isoniazid metabolism
Part A Pharmacokinetic Processes
 Induction of hepatic enzymes by drugs
 example:

phenytoin－steroids, nifedipine
 Inhibition of hepatic enzymes by drugs


example:
verapamil－diazepam
肝药酶诱导剂对双香豆素血浓度及凝血作用的影响
Part A Pharmacokinetic Processes
 3.4 Excretion
 Removal of a drug from the body via a
number of routes.
 Elimination of drugs from the body
 Action on excretory organs
Part A Pharmacokinetic Processes
 3.4 Excretion
 (1) Excretion routes






Kidney
Bile
Lung
GI tract
Milk
Secretion glands
Part A Pharmacokinetic Processes
 (2) Renal excretion






Glomerular filtrattion
renal blood flow
Active tubule secretion
specific carriers / competition
Passive tubule reabsorption
urine pH, urine flow
Part A Pharmacokinetic Processes
 (3) Bile excretion
 Carrier-mediated active
 transport
 Hepato-enteral circulation
Part A Pharmacokinetic Processes
 3.5 Elimination and Accumulation
 Elimination（消除）:



Metabolism
Excretion
Distribution (stored in fat, hair, etc)
 Accumulation（蓄积）:

Dosing rate > elimination rate