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Chapter III Pharmacokinetics

DURGE RAJ GHALAN


ghalan_raj@hotmail.com
Learning Objectives

1. Describe the physicochemical factors that influence


the absorption of drugs from enteral and parenteral
routes of administration, their distribution within
the body, metabolism (or biotransformation) and
their routes and mechanism of excretion (ADME).
Metabolism and Excretion are called Elimination
2. Explain how dose, bioavailability, rate of
absorption,
apparent volume of distribution, total clearance and
elimination half-life affect the plasma concentrations of
a drug after administration of a single dose.

3. Describe the factors that determine the time-course


of systemic accumulation of a drug administered by
infusion or multiple doses.
tissues target of drug liver or extrahepatic
binding and storage sites of action biotransformation

Distribution Metabolism
Absorption Excretion
free drug Metabolites
sites of drug
administration systemic
circulation binding drug

Fig. 3-1 Schematic representation of the ADME process of a drug. Drug was
absorbed from the sites of administration into the systemic circulation, in which
they reversibly bind to albumin or other proteins. The bound drug is inactive,
therefore it is limited its systemic distribution, metabolism and excretion. Only
free drug is able to cross membrane to reach tissues, sites of drug action and be
metabolized or excreted.
Transport Across Cell Membranes

1. Passive transport
2. Active transport
3. others: endocytosis or pinocytosis,
facilitated diffusion,
ion-pair transport
1. Passive transport

a. Passage through lipid cell membrane by dissolution


in membrane, simple diffusion and filtration.
b. rate dependent on concentration gradient and lipid:
water partition coefficient of drug.
c. rate markedly higher for nonionized form of weak
electrolyte because of its higher lipophilicity than
the ionized form.
the characteristics of passive transport:
a. no carrier requirement
b. no energy requirement
c. no saturability
d. no competitive inhibition by cotransported
compounds
e. the concentration of the free drug is the same on
both sides of the membrane at the steady state.
1. Therefore, the transmembrane distribution of a
weak electrolyte is usually determined by its
pKa and the pH gradient across the membrane.
2. The ratio of nonionized to ionized drug at each
pH is easily calculated from the Herderson-
hasselbalch equation.
Weak Electrolytes and Influence of pH
Herderson-hasselbalch equation
pKa :
pKa is the pH at which nonionized form
of the drug is equal to ionized form of the
drug.
pKa of a drug is determined by the
physicochemical property of the drug.
[X] 1000• [X]
HA A - + H+
plasma pH = 7.4

Lipid mucosal barrier

(ion trapping) gastric juice pH = 2.4

HA A - + H+
[X] 0.01• [X]

weak acid HA A - + H+ pKa=4.4


nonionized ionized

Fig.3-2 Lipid mucosal barrier acts as an ion trapping .


Ion trapping is significant for many weak acid or base drugs. For example, when a weak
acid drug (pKa=4.4) is dissolved in the gastric juice (pH=2.4), its concentration difference
of ionized drug between both sides of lipid mucosal barrier is 100,000 times because the PH
value of plasma is 7.4. Acidic drugs are well absorbed in the acidic medium of the stomach,
however it is better for the absorptions of basic drugs in the alkaline medium of the small
bowel.
Summary

1. More of a weak acid will be in the lipid-soluble


form at acid pH, while more of a basic drug will be
in the lipid-soluble form at alkaline pH.
2. This principle can be applied in the absorption,
distribution and in the manipulation of drug
excretion by the kidney.
Question ?

Somebody was poisoned by overdose


administration of Phenobarbital (weak acid),
how to accelerate the excretion of the drug ?

Sodium bicarbonate , alkaline urine


ammonium chloride , acidic urine
2. Active transport

a. Passage facilitated by an energy-dependent


membrane carrier mechanism such that transport
can occur against a concentration gradient.
b. Passage characterized by the requirement of
energy, saturability, selectivity and competitive
inhibition by cotransported compounds.
c. Transporters include the family of ATP-dependent
proteins.
Absorption of Drugs

1. general determinants of absorption rate


Lipid solubility, ionization, size of the molecule,
and presence of a transport mechanism.
Others like concentration gradient, blood flow, and
surface area of absorption site.
2. routes of drug administration
a. Oral (p.o.) ingestion
1) convenient route for administration of solid as well
as liquid formulations.
2) first-pass elimination: absorbed drug passes via
portal circulation through liver which may clear
substantial fraction and thus decrease bioavailability.
What is first-pass effect?

A drug that is absorbed from the stomach and intestine must


first pass through the liver before it reaches the systemic
circulation. If the drug is metabolized in the liver or excreted
in
the bile, some of the active drug will be inactivated or diverted
before it can reach the general circulation and be distributed to
its sites of action. If the metabolic or excretory capacity of the
liver for the agent is great, bioavailability will be substantially
decreased. That is so called first-pass effect.
3) Additional variables which may influence rate
and extent of absorption include disintegration
and dissolution of solids, acidity of gastric
contents, gastric emptying rate, intraluminal
biotransformation by host or bacterial enzymes,
dietary contents, and presence of other drugs.
b. Parenteral Injection
1) Intravenous(i.v.) Injection: complete bioavailability; drugs
only given in sterile solution; important when immediate
effect required; increased risk of toxicity.

2) Subcutaneous(s.c.) and Intramuscular(i.m.) Administration:


more extensive absorption of high molecular weight, polar
molecules than by p.o. route; absorption rate can be
manipulated by formation, e.g. rapid from aqueous solution,
slow from suspension or solid pellet.
c. Pulmonary Inhalation
1) Rapid absorption of drugs in gaseous, vaporized
or aerosol form.

2) Absorption of particulates depends on particle


size which influences depth of entry in pulmonary
tree.
d. Topical Application
1) Usually for local effect
2) Absorption through mucous membrane may be
rapid
3) Absorption through skin generally slow; enhanced
by increased lipophilicity, by damage to
stratumcorneum, and by increased blood flow.
e. Sublingual Administration
For example: Nitroglycerin

f. Rectal Administration preclud


Distribution of Drugs

A. Tissue difference in rates of uptake of drugs.

1) Blood flow: distribution occurs most rapidly into


tissues with high blood flow (lungs, kidneys, liver,
brain) and least rapidly in tissues with low flow
(fat).
2) Capillary permeability: distribution rates
relatively slower into CNS because of tight
junction between capillary endothelial cells,
endothelial cell efflux transporters, insignificant
membrane aqueous pores, and juxtaposed glial
cells around endothelium.interstitial
B. Differences in tissue/blood ratios at equilibrium
1) Dissolution of lipid-solution drugs in adipose tissue
2) Binding of drugs to intracellular sites
3) Plasma protein binding
Elimination of Drugs

A. Biotransformation or metabolism
1) site of biotransformation
liver (mainly)
gastrointestinal tract, kidneys, lungs

enzyme: cytochrome P450 (CYP) (in liver)


others such as cholinesterase (AchE),
and monoamine oxidase (MAO)
2) Major pathways of biotransformation
a. Phase I: Oxidation
Reduction
Hydrolysis
primary oxidative enzymes, the cytochrome P450s

b. Phase II: Conjugation Reactions


phase Ⅰ phase Ⅱ

Fig.3-3 The proportion of drugs metabolized by major phaseⅠand phaseⅡenzymes.


The relative size of each pie section stands for the estimated percentage of phase I or
phase II metabolism via different enzymes shown in the figure. In many cases, more than
one enzyme is involved in a particular drug's metabolism.In this figure: CYP, cytochrome
P450; GST, glutathione S-transferases; NAT, N-acetyltransferases; ST, sulfotransferases;
TPMT, thiopurine methyltransferase; UGT, UDP-glucuronosyltransferases.
NADP+ NADPH

flavoprotein flavoprotein
(reduce) (oxidized)

P450 Fe3+ P450 Fe2+

RH2 RH2 O2

H2O
P450 Fe3+ O2 P450 Fe2+

RH2
RH2 RHOH
(parent drug) (oxidized product)

Fig.3-4 Cytochrome P450 cycle in drug oxidations.


In the figure, O2: oxygen RH2: parent drug; RHOH: product.
Pro-drugs: pro-drugs are pharmacologically
inactive compounds, are biotransformed to a
therapeutic agent(or active drug).
3) factors affecting drug metabolism
a. genetic variation
b. disease factors
c. age and sex
d. environmental determinants
inhibition of drug metabolism, and
induction of drug metabolism
Induction of CYP: Up-regulate the enzyme
e.g. Barbiphenyl ( 苯巴比妥 ) induce CYP
decrease drug concentration tolerance( 耐受性 )

Inhibition of CYP: Down-regulate the enzyme


B. Excretion
1) routes of excretion
a. Urine (renal excretion)
b. Biliary and Fecal Excretion
c. Breath (pulmonary excretion)
d. Minor routes: sweat, saliva, tears, reproductive
fluids, breast milk
1. renal excretion
1) glomerular filtration ( 肾小球滤过 )
2) passive tubule reabsorption ( 肾小管被动重吸收 )
3) active tubule secretion ( 肾小管主动分泌 )
1) glomerular filtration :
Molecular Weight (MW) <20,000
2) passive tubule reabsorption
a. passive transport
b. pH-dependent: reabsorption of weak electrolytes
is dependent on urinary pH( raising the pH promotes

excretion of acids, impairs excretion of bases).


3) active tubule secretion
active transport
carrier-mediated
weak acid carrier, and weak base carrier
competitive inhibition by cotransported compounds
weak acid drugs: probenecid, penicillin, indomethacin,
acetazolamide, aspirin, furosemide, cefaloridine,
methotrexate, sulfinpyrazone, salicylic acid, thiazides.

weak base drugs: amiloride, morphine, 5-HT,


histamine, quinine, dopamine, pethidine, tolazoline,
triamterene, mepacrine
Time Course of Plasma Concentrations

A. Relationship between plasma concentration


and drug effect
minimum effective concentration, latency,
duration of effect, time and magnitude of peak effect
MEC for
adverse response
peak concentration
drug concentration

therapeutic
dosage window
intensity

duration of effect MEC for


desired response
onset of effect
area under the curve , AUC

latency time

Fig. 3-5 The blood drug concentration-time curve of a single dosage

administered extravenously. MEC: minimal effect concentration.


open one compartment model open two compartment model

central central k1 2 peripheral


D0 compartment D0 compartment compartment
k2 1

ke ke

logC logC
-k
e/2


.3

/2.3

-α /2.30
03

03

3
t t

Fig.3-6 Schematic representation of the compartment models and


their concentration curves. In the two open compartment model,
the central compartment consists of intravascular fluid and highly
perfused tissues , including heart, liver, brain, lung and kidney.
B. Time-course of plasma concentrations for
a single dose
1. Case with highly rapid absorption relative to elimination
a. Single compartment model
1) First-order kinetics (elimination)

d c dt = −K eC
Ke (elimination rate constant):
fraction eliminated per unit time
(first-order kinetics)
C − ket
logC 1
C t = C0e logC t = logC 0 −
2.303
ket

t t

Fig. 3-7 Concentration-time curve and logarithm concentration-time


curve of the first-order kinetics.
First-order kinetics (elimination)

1. Elimination rate from plasma is proportional to


plasma concentration
2. Plasma half-life (t1/2=0.693/ke) is constant and
independent of dose.
3. Most drugs in the body were eliminated by first-
order kinetics.
2) zero-order kinetics (elimination)

d C dt = −KC 0

0
C =1 d C dt = −K
zero-order kinetics

C C t = C 0 − K⋅ t logC

t t

Fig.3-8 Concentration-time curve and logarithm concentration-


time curve of the zero-order kinetics.
zero-order kinetics (elimination)

1. Elimination rate is constant.


2. Plasma half-life (t1/2 =C/2ke) is not a constant
and is dose-dependent.
3. few drugs such as phenytoin, salicylic acid and
ethanol, when used in large dose, were
eliminated by zero-order elimination. While the
plasma concentration decrease, the zero-order
elimination transfer to the first-order elimination.
Pharmacokinetic parameters
Most drugs in the body obey first-order elimination
C = C e(5)
t 0
− ket
logC = logC −
t 0
1
k t e
2.303
C logC

(6)

t t

log Ct= Y, log C0=a , -ke / 2.303=b , t 为


X,

Y= a + b X equation
from the pharmacokinetic experiment,
1. we can detect Ct.
2. then, we calculate C0 and Ke
3. and then, we can get the following
pharmacokinetic parameters
A. apparent volume of distribution (Vd)

Vd = D 0 C 0 = D C
1. fluid compartments of 70-kg subject in liters and percent
of body weight: plasma volume 3 L, blood volume 5.5 L,
extracellular water 12 L, total body water 42 L.
2. Vd = 5L, drug distribute in plasma ;
Vd = 10~20L, drug distribute in extracellular ;
Vd = 40L , drug distribute in total body water;
Vd = 100~200L, drug distribute in tissue.
3. we can predict characteristic of drug from Vd.
e.g. high Vd, high lipid solubility, distribute in
tissue, eliminate very slowly.
4. the plasma half-life(t1/2) of a drug is directly
proportional to Vd, and inversely proportional to
total clearance (Cl) ; for a given Cl, the higher the
Vd, the longer the t1/2.
CL = Ke ⋅ Vd t1/2=0.693/k
e
B. Plasma clearance, (CL)

CL = Ke ⋅ Vd

CL = C0 ⋅V d AUC = D 0 AUC
Vd & Cl

1. CL total = CL hepatic + CL renal + CL others


2. Vd of a drug is determined by physicochemical
characteristic of the drug.
3. CL total Ke CL = Ke ⋅ Vd
C. Plasma half-life(t1/2)
The half-life( t1/2) is the time it takes for the
plasma concentration or the amount of drug in
the body to be reduced by 50%.
t1/2 , Ct / C0=1/2
1) First-order kinetics, one compartment model
− ket
d c dt = −K eC C t = C0e
C t=C 0/2 t1/2=0.693/ke

Plasma half-life (t1/2=0.693/ke) is constant


and independent of dose. (11)
Table 3-2 The Relationship between the Rest Dose ( or Accumulation
Dose) and the t1/2 for Medication a First-order Kinetics Elimination Drug

number after a single iv regular medication: every t1/2 interval


of t1/2 rest amount dose give a single dose
rest dose before iv accumulation dose
after iv

iv 100%×(1/2)0 = 100% 0% 100%


1 100%×(1/2)1 = 50% 50% 150%
2 100%×(1/2)2 = 25% 75% 175%
3 100%×(1/2)3 = 12.5% 87.5% 187.5%
4 100%×(1/2)4 = 6.25% 93.8% 193.8%
5 100%×(1/2)5 = 3.12% 96.9% 196.9%
6 100%×(1/2)6 = 1.56% 98.4% 198.4%
∞ 100%×(1/2)∞≈0% 100% 200%
2) zero-order kinetics, one compartment model

d C dt = −K C t = C 0 − K⋅ t

Ct=C0/2 时, t1/2 =C0/2ke

Plasma half-life (t1/2 =C/2ke) is not a


constant and is dose-dependent.
Bioavailability (F, 生物利 用
度 )

bioavailability
The amount of the drug that reaches
the systemic circulation can be expressed
as a fraction of the dose absorbed (F).
This fraction is often called bioavailability.
Bioavailability (F) is determined experimentally by
measuring AUC of dosage form of drug given by
one route and comparing it to AUC of same dose of
drug under conditions of complete absorption, i.e.
given i.v.
AUC: Area under plasma concentration
Bioavailability (F)

AUC(ev)
F £½
AUC(iv)
¡Á100£¥

AUC(test)
F £½ ¡Á100%
AUC(standard)
CmaxA increase risk of toxicity
MEC for
adverse response

CmaxB
plasma drug concentration

MEC for
CmaxC desired response

C
B
A

TmaxA TmaxB TmaxC time

Fig. 3-9 The theoretical plasma concentrations resulting over a period of time after
the oral administration of three different formulations of the same dose of the same
drug. Each drug has a different speed of absorption but has the same AUC.
First-order elimination and multiple dose
峰浓度
1 dose / t1/2 (Cssmax) 2 dose/t1/2 after 1dose/t1/2
2.0 2.0

• 1.5Fig. 3-11 Schematic representation of fundamental pharmacokinitic 1.5


dose

relationships for repeated administration of drugs. In the figure: (A) a drug is


adiminstered in one dose at interval of t1/2 , and (B) a drug is given in two 1.0
1.0
doses firstly and then added in one dose谷浓度
at intervals of t1/2.
Iv drip 1.44t1/2dose iv after iv drip
(Cssmin)
0.5 0.5

0 1 2 3 4 5 6 t1/2 0 1 2 t1/2

(A) (B)

Fig. 3-10 Schematic representation of fundamental pharmacokinetic relationships


for repeated administration of drugs. In the figure: (A) a drug is administered in
one dose at interval of t1/2 , and (B) a drug is given in two doses firstly and then
added in one dose at intervals of t1/2.