3

Pharmacokinetics
..

,
,,

1. -

2.

3.

4.

5.

6.

Phase I Phase II reaction

7.
8. Clinical

pharmacokinetics clearance, volume of

distribution bioavailability

9. Clinical pharmacokinetics

1 Physiocochemical factors in transfer of drugs

across membranes

2 Drug Absorption
3 Drug Distribution
4 Drug Metabolism
5 Drug Excretion

6 Basic clinical pharmacokinetics

(absorption), (distribution),
(metabolism or biotransformation)

(excretion)
Pharmacokinetics
Locus of action
receptors
Bound

Tissue
Reservoirs

free

Free

Bound

Systemic
circulation

Absorption

Free drug

Excretion

Bound drug

metabolites

Biotransformation

 3.1 Schematic representation of the interrelationship of the

absorption, distribution, binding, biotransformation, and excretion
of a drug and its concentration at its locus of action.

Physicochemical factors in transfer of

drugs

across

membranes

Barrier
aqueous compartment

cell membranes


cell membrane Cell membrane

lipid bilayer amphipathic lipid 2

hydrophilic hydrophobic
hydrocarbon chain

Small molecules molecule cell

membrane 4

1. Diffusion lipid bilayer

2. Diffusion aqueous pore lipid bilayer

3. transmembrane carrier protein

cell membrane

4. Pinocytosis

4 diffusion lipid bilayer

carrier mediated transport

diffusion aqueous pore

aqueous
pore pinocytosis

pH and Ionisation

weak acid weak base

ionised form
nonionised form pH
weak base

BH

B + H

weak acid

AH

A + H

ionised form (BH A ) form lipid

+

solubility
membrane

nonionised form (B AH) lipid solubility

membrane nonionised ionised form

weak base weak acid pH pKa

Henderson-Hansselbalch equation

weak base

pKa =

pH + log[BH ]/[B]

weak acid

pKa =

pH + log[AH]/[A ]

2 Drug Absorption

Drug Absorption

(site of administration) plasma absorption

(intravenous injection)

 (Route of administration) oral,

sublingual, rectal, application to other epithelial surface (skin,

nasal mucosa), inhalation, injection (subcutaneous, intramuscular,

intravenous, intrathecal injection)

1. Gastrointestinal motility
2. Splanchnic blood flow

3. Particle size and formulation

4. Physicochemical factor
Bioavailability

Systemic circulation systemic

circulation

portal circulation systemic circulation

systemic circulation

systemic

circulation first pass metabolism presystemic

metabolism bioavailability
Bioavailability
absorption local metabolic degradation 3.1
presystemic circulation

 3 Drug Distribution

Bloodstream

fluid compartment

physiological factors physicochemical properties

cardiac output

blood flow (well perfused

organ) , ,
, , ,

blood flow

distribution

1. Permeability across barrier

2. Drug binding
3. pH partition

4. Fat : water partition

Volume

of

distribution

(Vd)

Volume of distribution volume fluid

plasma (Vd is defined as the volume of

fluid required to contain the total amount, Q, of the drug in the

body at the same concentration as that present the plasma, C p)
Vd

Q/Cp

Vd apparent volume volume

Vd parameter
Vd

plasma Vd
plasma

4 Drug Metabolism

Drug metabolism 2

1. Phase I reaction
oxidation, reduction, hydrolysis

reactive group products

chemically reactive toxicity
parent drugs
2. Phase II reaction

conjugation

inactive compound

Phase lipid solubility

Phase I Phase II reactions

phase I smooth endoplasmic reticulum (SER)

phase II cytosol
SER microsomal

enzyme homogenization differential

centrifugation ER fragment
sediment microsomal fraction

 Metabolize hepatocyte plasma

membrane polar molecule metabolize

unchanged
form

1. Enzyme

Induction

2. Enzyme

Inhibition

3. Genetic

polymorphisms

4. Disease
5. Age

and

Gender

5 Drug Excretion
5.1

Renal

Excretion

1. Glomerular filtration

2. Active tubular secretion

3. Passive tubular reabsorption

5.2

Biliary

excretion

and

enterohepatic

circulation

6 Basic clinical pharmacokinetics

Clinical pharmacokinetics

(Pharmacological or toxic response)

()

9

 Clinical pharmacokinetics

(standard dose)

Pharmacokinetics

Pharmacokinetic parameter

1. Clearance (CL)

2. Volume of distribution (Vd)

3. Bioavailability
6.1

Clearance

Drug clearance (CL)

creatinine clearance (CLcr)

creatinine
creatinine

, , ,
Clearance route Rate of

elimination organ
biological fluid

10

Systemic clearance clearance

CL route
CLrenal + CLliver

+ CLother

CLsys =

Clearance

(route)
plasma (biological fluid)
CL

Rate of elimination
C

CL biological fluid (
plasma)
CL volume per unit of time ml/min

CL

(fraction)
1 order kinetic
st

(Capacity limited elimination)

Zero order kinetics

alcohol, phenytoin, aspirin
saturation kinetics protein binding,
hepatic metabolism active renal transport

11

6.2

Volume

of

distribution

Volume of distribution (Vd)

plasma
Vd
6.3

Design

Maintenance

and

Amount of drug in the body

C

optimization

dose

of

dosage

regimens

(MD)

Maintenance dose

plasma steady state concentration

intravenous infusion
steady state plasma

(Complete

bioavailability) (steady state

concentration, CSS) (rate of drug elimination

rate out) (dosing rate rate in)

Dosing rate

Rate of elimination
Dosing rate

Rate of elimination
=

CL x CSS

CL x CSS

CL x TC

bioavailability 100%
bioavailability (F)
12

F x Dosing rate

CL x CSS

Dosing rate

CL x CSS

CL x TC

Intermittent dose

Maintenance dose

dosing interval (T)

Loading

Dosing rate x

dose

(LD)

series target level

concentration loading dose

t1/2
steady state 3-4 t1/2

loading dose
loading dose


Loading dose
Loading dose

Loading dose

=
=

Desired plasma level x Vd

TC x Vd

13

 loading dose rate of

administration

14

15

Hardman JG, Goodman Gilman A, Limbird LE, ed.

Goodman & Gilmans The pharmacological basis of therapeutics.

9 ed. New York: The McGraw-Hill; 1996.
th

Katzung BG, ed. Basic and clinical pharmacology, 8 ed.

th

New York: Lange medical books/McGraw-Hill; 2001.

Rang HP, Dale MM, Ritter JM, Pharmacology. 4 ed.

th

Edinburgh: Churchill Livingstone; 2000.

Hedaya M (subject specialist). Pharmacokinetic simulations

version 2.0. PCCAL CAI. Developed by Washington state

university and department of pharmacy and pharmacology;

University of Bath. 1999.

16

17