Transcript PRINCIPLES OF PHARMACOLOGY

Chapter 2
Pharmacokinetics
Department of pharmacology
M. Y. Liu
Pharmacokinetics
Transmembrane transport
Processes of drug in the body
Basic concepts of pharmacokinetics
Part 1
Transmembrane transport of drugs
LOCUS OF ACTION
“RECEPTORS”
Bound
ABSORPTION
Free
TISSUE
RESERVOIRS
Free
Bound
Free Drug
Bound Drug
SYSTEMIC
CIRCULATION
BIOTRANSFORMATION
EXCRETION
The structure of cell membrane？
How to transport it？
Transmembrane transport
Procedure of permeating through the
various barriers
Such as: various cell membrane
the walls of the capillary
the walls of the intestine
blood-brain barrier
placental barrier
Ability that the drug permeates through
various membranes
Two types of transmembrane transport
Passive transport (down hill movement)
 According to the concentration gradient
of the permeating drug, the direction of
diffusion was from higher concentration
to lower concentration.
Small molecules: membrane pores
Large molecules: lipid diffusion
Not requiring energy
Having no saturation
Having no carriers
Not resisting competitive inhibition
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment
such as: fluid of body
fluid in cell
blood, urine
Generally speaking
The drugs which are Unionized, low
polarity and higher lipid solubility are
easy to permeate membrane.
The drugs which are ionized, high
polarity and lower lipid solubility are
difficult to permeate membrane.
Effect of the environment PH on drug transportation
Most of drugs are weak acids or
weak bases.
The ionization of drugs may
markedly reduce their ability to
permeate membranes.
The degree of ionization of drugs is
determined by the surrounding pH
and their pKa.
For acids：
Handerson-Hasselbalch
Equation
The pKa is the pH at which the drug is 50% ionized.
For bases：
pH和pKa算术差的变化，
就会导致解离与非解离药
物浓度差的指数变化，因
此pH的微小变化将显著的
影响药物的解离和转运。
 When the pH is different from the intracellular and
extracellular membrane and the passive transport of
weak acid/base drugs are in the balance, the drug
concentration of intracellular and extracellular membrane
are compared as below：
eg. For weak acid drug whose pKa is equal to 5.4
unionized
plasma
pH=7.4
[HA]
1
Gastric juice
pH=1.4 [HA]
1
ionized
[A-]
100
[A-]
0.0001
When drug concentration of the intracellular and extracellular
membrane are balanced, the total concentration isn’t equal; while the
concentration of unionized drug are same .
total
101
1.0001
pKa= 3.4
 When the pH of the intracellular and extracellular are
not equal, the total concentration of the drug in the
two sides of membrane are given by the equation as
below:
For acid:
For base:
Q：What kind of drugs can be excreted to the
latex which pH is tend to acidity?
The other forms of passive transport
Filtration:
water solubility
small molecular
Facilitated transport：
 （in fact it is a kind of passive transport）
 Transport from high concentration to low
concentration
Not requiring energy
Requiring carriers
eg the absorption of Vitamin B12 from GI tract
The transportation of Glucose to the intra cellular
membrane of red blood cells.
Active transport
 permeating membrane from lower
concentration to higher concentration.
 Requiring energy
 Requiring carriers
 Be Saturable
 H aving competitive inhibition
Such as : peptide, amino acid
The conditions which need active transport
Na+-K+-ATPase
The transmitters were concentrated
in the vesicle.
The excretion and secretion of
renal tract
Active transport can concentrate drugs in certain
organ or tissue (the iodine pump )
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Sugars, amino
acids, vitamins
Diffusion
Bulk Flow
Most drugs are
Ion Pairabsorbed and
distributed by
Facilitated Transport
diffusion.
Endocytosis
Active Transport
药物代谢动力学
The processes of drugs（ADME）
Pharmacokinetics
• movement of drugs in the body
• what the body does to the drug
“ADME”
Absorption Distribution Metabolism Excretion
The disposition to drugs by living
systems can be divided into four related
duration:
吸收（Absorption）
分布（Distribution）
代谢（Metabolism）
排泄（Excretion）
ADME 系统
Metabolism + Excretion = Elimination
Absorption + Distribution + Excretion = Transportation
Metabolism= Transformation
 Absorption is the transfer of a drug from its
site of administration to the blood stream.
Characters：
Most of drugs are absorbed by the way of
passive transport.

Intravenous administration has no
absorption.
 The absorptive speed affects the time of
appearing effect.
The absorptive extent affects the intensity of
action.
Factors affecting absorption:
 drug properties:
lipid solubility、Molecular Weight,polarity,etc.
 Routes of Administration
(important):
 Enteral; parenteral
 Other:
 Blood flow to the absorption site;
 Total surface area available for absorption
 Contact time at the absorption surface
 Affinity with special tissue
Enteral administration
Oral
Sublingual
Rectal
Oral administration
First Pass Elimination (首关消除,首关代谢，首关效应）
Before the drug reaches
the systemic circulation,
the drug can be
metabolized in the liver
or intestine. As a Result,
the concentration of drug
in the systemic circulation
will be reduced.
FIRST PASS ELIMINATION
Metabolism in the liver
Buccal cavity
Stomach
Intestine
Rectum
Portal
vein
Vena
cava
 Sublingual Administration (硝酸甘油)

Rectal Administration (水合氯醛)
Buccal or rectal administration are ways to
by-pass the liver and avoid “first pass”
Buccal cavity
Buccal
Stomach
Vena
cava
Intestine
Rectum
Rectal
 Parenteral
Inhalation
注射给药
静脉内
肌内
皮下
intravenous (IV)
intramuscular (IM)
subcutaneous (SC)
other：intranasal(经鼻给药), intraventricular(心室
内给药), Transdermal（经皮给药）
Intravenous administration has no
absorption phase.
According to the rate of absorption：
Inhalation→Sublingual→Rectal→intramusc
ular→subcutaneous→oral→transdermal
Example: 硝酸甘油（Nitroglycerin）
Route
Onset
IV
immediate
SL
1-3 min
Transdermal
40-60 min
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.
药物的体内过程
分布
•Factors affecting drug distribution：
•Blood flow
•Capillary permeability
•Capillary structure
•Drug structue
•Binding of drugs to proteins
•Most drugs found in the vascular compartment are
bound reversibly with one or more of the
macromolecules in plasma.
•Many acidic drugs bind principally to albumin，
while basic drugs frequently bind to other plasma
proteins such as lipoproteins and α1-acid glycoprotein
(α1-AGP)。
药物与血浆蛋白结合（Protein binding）
Characters：
Drugs ordinarily bind to protein in a reversible fashion
and in dynamic equilibrium. Those bound to protein are
called bound drug, and those unbound to protein are
called free drug.
Only the unbound drugs can diffuse through the
capillary wall, produce its systemic effects, be
metabolized and be excreted.
Bound drugs lose pharmacological activity momentarily，
and act as a drug reservoir.
Having saturation and competitive inhibition.
Patient with low plasma protein (uraemia,
hepatic disease) or old people with low
albumin in plasma ,their percentage of
protein binding may be changed, amount of
unbound drug increases, effect precipitate.
interaction
When the two kind of drugs that
possess the higher protein binding rate are
associated for clinical using, the drug
interaction may occur.
If the amount of unbound drug displaced
from plasma protein increases, the unbound
drug concentration and effect also
increases, and perhaps, produce toxicity.
Such as: phenylbutazone (保泰松)
Dicoumarin （双香豆素）
How to salvage the toxic effect of barbital drugs?
With NaHCO3
Alkalizing plasma to force the
weak acidic drug (barbital drug)
from brain to plasma.
Alkalizing urine to increase the
excretion of the drugs
Biological barriers
bound/ ionized drug can not
pass through the BBB!

血脑屏障
Blood Brain Barrier
•
•
毛细血管内皮
细胞联结紧密，
管壁外被星型
胶质细胞包围。
炎症可改变通透性
14C-Promazine
14C-Promazine
Quaternary Analog
+
胎盘屏障
Placental barriers
生物膜屏障（membrane
barriers)
having no barrier effect on drug
transport, but the pregnant women
should especially pay attention.

Blood-eye
barriers
 Metabolism：
most often eliminated by biotransformation Drugs
are and /or excretion into the urine or bile.
The liver is the major site for drug metabolism.
Two phase of metabolism:
Phase I：oxidation (氧化) 、hydrolysis (水解反
应 ) 、reduction(还原)
Phase Ⅱ：conjugation(结合反应 )： glucuronic
acid（葡萄糖醛酸） sulfuric acid
glycin （甘氨酸）
Changes after metabolism:
The pharmacological activity of the drugs is
decreased or lost, while certain drugs must metabolize
to exert the reaction.
Variety of drug activity after
biotransformation:
A
active drug
B inactive drug
inactive metabolites
active/enhanced activity
Such as :
P-450
Cyclophosphamide(环磷酰胺)
blood
tumor
aldophosphamide（醛磷酰胺）
Phosphamide mustard（磷酸胺氮芥）
C active drug
Phenacetin非那西丁
active product
Acetaminophen (paracetamol)
对乙酰氨基酚（扑热息痛）
(prototype drug or parent drug)
D no toxic or less toxic drug
toxic
metabolites
Isoniazid(Rimifon)
Acetylisoniazid
INH 异烟肼
Acetyl INH
mutagenicity致突变
teratogenicity致畸变
carcinogenicity致癌
hepatotoxicity肝毒性
E consequent
1)Lipophilic xenobiotics (or drugs) are
transformed to more polar and hence
more readily excretable products.
Lipophilic drug
hydrophilic compound
(lipid soluble
water soluble)
2)Large molecule
small molecule
Enzyme system classification:
Special enzyme: AChE, MAO
Unspecial enzyme:
Cytochrome P450 Enzymes
properties:
low selectivity and specificity
saturation
large variability
induced or inhibited by drugs---enzyme
induction or enzyme inhibition
Induction and inhibition of enzyme
Some drugs can increase the rate
of synthesis of cytochrome P450
enzymes .
This enzyme induction can enhance
the clearance of other drugs.
Inducing agents are:
rifampicin(利福平),
carbamazepine（卡马西平),
phenobarbital(苯巴比妥),
phenytoin(苯妥英)
Other drugs can inhibit cytochrome
P450 enzymes.
This is usually seen rapidly after
drug exposure.
Enzyme inhibiting agents are:
Cimetidine(西咪替丁)
chloromycetin （氯霉素）
Isoniazid（异烟肼）
excretion
Excretion is a transport procedure which the
prototype drug (or parent drug) or other metabolic
products are excreted through excretion organ or
secretion organ.
Principal organs：
Kidney，biliary system, lungs, intestines, milk,
skin, sweat glands
Renal Excretion
Filtration
Secretion
Reabsorption
Renal excretion
glomerular filtration
Protein bound drugs are not
filtered !!
Reabsorption
high lipid-soluble ,lower polar.
unionized drug easy to reabsorb
high water–soluble, high polar
ionized drug uneasy to reabsorb
Active secretion of tubule
Changing pH of tubular lumen
fluid, may change absorption
extent of drug in urine.

acidic urine =
alkaline drugs eliminated
acid drugs reabsorbed
alkaline urine =
- acid drugs eliminated
- alkaline drugs absorbed
renal disease/ decreased clearance
affects drug dosage
affect of uric pH on dissociation of drug
weak acid drug
dissociation large
weak basic drug
dissociation large
weak acid drug
dissociation small
weak basic drug
dissociation small
alkaline urine
excretion accelerate
acid urine
excretion fast
acid urine
excretion reduce
alkaline urine
excretion slow
※ competitive inhibition
when two drug pass through same pathway,
using same carrier ,competitive inhibition
can occur.
For example 1 Penicillin and Probenecid
Using acid pathway
Decreasing excretion of penicillin
Increasing action duration of enicillin
2 Ethacrynic acid and uric acid
Decreasing uric acid excretion
Increasing accumulation of uric acid
Inducing gout occur
Initially penicillin was in critically short supply 
probenecid(丙磺舒) (a simple benzoic acid derivative was
developed to block rapid excretion of penicillin)
Today used as an uricosuric agent (also prevents uric acid
reabsorption).
for example :
Streptomycin（链霉素） 0.5g Q6H
High concentration in urine fluid .
100 time higher in urine than in blood .
Treatment inflammation in uric tract.
Sulfonamides in acid urine
Concentration
Crystallization
GI tract excretion
肠肝循环（hepatoenteral circulation)
liver
blood
bile
gall bladder
GI tract
Hepatic Excretion
Drugs can be excreted in bile,
especially when the are
conjugated with
glucuronic acid
Bile duct
Intestines
Portal
vein
Drug is absorbed  glucuronidated or sulfatated in the liver and secreted
through the bile  glucuronic acid/sulfate is cleaved off by bacteria in GI
tract  drug is reabsorbed (example steroid hormones, contraceptives)

latex
The concentration of basic drugs are higher
than acidic drugs in the latex.
 eg. morphine、Propylthiouracil(丙基硫氧嘧啶)

Pulmonary excretion

Sweat gland, lacriminal
Part 3
basic concepts of pharmacokinetics

Time-concentration curve

Two kinds of elimination kinetics
 Compartment model
 Pharmacokinetics parameters
 Pharmacokinetics of single vs multiple dosing
Two levels
Three durations
Three points
•药物消除半衰期（Half-Life，t1/2)
The time it takes for half of drug
to be eliminated from the body.
Give
1
2
3
4
5
6
100 mg of a drug
half-life ………….. 50
half-lives………… 25
half-lives …….…..12.5
half-lives ………… 6.25
half-lives ………… 3.125
half-lives …………. 1.56
5 half-lives = 97% of drug eliminated
当仃止用药时间达到5个药物的t1/2时，药物的血浓度
（或体存量）仅余原来的3%，可认为已基本全部消除。
First order kinetics
K为消除速率常数，是药动学中的一
项重要参数，它并不随时间而发生变化，
是药物本身固有的属性。
two-kinds of elimination kinetics
First-order elimination kinetics
More quickly drug in plasma eliminates
from body, higher concentration of the
drug is, so it called fixed percentage
elimination.
 fixed half time.
 If the concentration’s unit is
expressed by logarithm, the c-t curve
is a beeline.
Most of drugs used by clinical dosages
are eliminated by first order kinetics.
Zero order kinetics
Characters of zero order kinetics
•The
eliminated rate has no relationship with the drug
concentration.
•The quantity of eliminated drugs in per unit of time are fixed.
• Having no fixed half life.
•If the concentration are expressed by numerical value, the Ct curve are a beeline.
•When drugs in the body are excessive to exceed the maxim
eliminative ability, the kinetics of the drug in the body is
according to zero order kinetics; while the concentration
descends to the range which the body can eliminate, the
kinetics will accord to first order kinetics.
Zero order
First order
Compartment model
Pharmacokinetic model have no
physiologic meaning, but can be
described schematically or
mathematically
According to elimination rate
constant(k) of drug in different
tissue and organ。
 房室模型
(compartment model)
 房室模型
(compartment model)
Apparent volume of distribution
(表观分布容积)
 Volume of distribution (Vd) relates
the amount of drug in the body to
the concentration of drug in blood or
plasma. （ L/kg, L ）
 Vd=Dosage/C(plasma)
Volume of Distribution
Plasma ~ 3 L
Blood ~ 5 L
Extracellular
fluid ~18 L
Total body
water ~50-60 L
confined to plasma distributed in body tissue
Bioavailability（F）：is defined as the
fraction of the administered drug
reaching the systemic circulation as intact
drug.
Bioavailabilty is highly dependent on both
the route of administration and the drug
formulation.
绝对生物利用度
口服等量药物AUC
F=
静注等量药物AUC
× 100%
相对生物利用度
F=
受试药AUC
标准药AUC
× 100%
The formulation of a drug also affects
its absorption:
BIOEQUIVALENCE
Drugs may have the same
bioavailability, but they may not be
bioequivalent (= have the same
pharmacological effect).
BIOEQUIVALENCE
AUC Formulation 1 = 100 mcg/ml/min
AUC Formulation 2 = 100 mcg/ml/min
BIOEQUIVALENCE
Drugs with same bioavailability may not have the same
bioequivalence. This normally is not as important as
pharmaceutical companies state, but it can become an issue
for drugs with a narrow therapeutic window.
% Oral bioavailability = AUC (po) X 100
AUC (iv)
= 50 mcg/ml/min X 100
100 mcg/ml/min
= 50%
Clearance
Another “constant” that describes
drug elimination
= volume of plasma “cleared” of drug
per unit time (mL/min)
• 清除率（clearance，Cl)
单位时间内有多少分布容积中的药物被清除
（单位：ml/min or L/hr)
计算公式：
Adjusting doses when clearance
has changed because of
disease or age
Time-concentration curve of continuous administration drug
Change of Css（稳态浓度）
Drug concentration of steady
state in blood
Dosing rate equals rate of
elimination after 4-5t½
drug concentration relatively
exhibits steady level
(concentration,Css), also it was
called as plateau(坪值）
Dosing rate =Rate of elimination
(If same intermittent doses are given)
CSS max: maximum concentration of
steady state（ Peak C）
Css min: minimum concentration of
steady state
Peak Time: It is a time achieving the
CSS max
Relationship between dosing rate and drug concentration in
steady state
Ass: amount of drug in the body
Css: concentration in steady state
R: dosing rate
Continuous repeating administration in
intravenous injection
Administration dose: D
Dosing interval: τ
In steady state:
 dosing rate=rate of elimination
R=Ass·k
Ass=Css·Vd
R=D/τ = Css·Vd·k = Css·Vd·0.693/t1/2
Css=1.44·t1/2D/(Vd·τ )
Ass=1.44·t1/2D/τ
Css=1.44·t1/2D/(Vd·τ )
Changing dosing interval 0.5t1/2,
t1/2,2t1/2, ;no changing dosage D, Css
change, while tss not
Css=1.44·t1/2D/(Vd·τ )
Changing dosage 2D, D, 0.5D; no
changing interval t1/2, Css change ,
while tss not
Loading dose
It is a first dosing amount that achieves
Css rapidly, before given routine dose
Loading dose=Amount in the body achieving
Css immediately following the loading dose
Loading dose is a beginning dose that
promptly raises the concentration of drug in
plasma to the target concentration
Generally speaking:
Oral administration: dosing interval is
t1/2 or so
Loading dose=Two times the amount
of routine administration dose
=Administrated dosage·2