PRINCIPLES OF

PHARMACOKINETICS

By
Dr. Girish M B
Associate Professor of Pharmacology
College of Medicine, KFU
 Learning Objectives

 Understand the processes involved and factors influencing the

disposition of a drug which includes (ADME) : Absorption,
Distribution, Metabolism, Excretion

 Explain how bioavailability, rate of absorption, apparent

volume of distribution, total clearance and elimination half- life
affect the plasma concentrations of a drug
 Pharmacokinetics

 Definition: Study of the time course of drug absorption,

distribution, metabolism, and excretion.

 Application of pharmacokinetic principles: Safe and effective

therapeutic management of drugs in an individual patient.
Routes of Drug Administration
 Routes of drug administration

Oral routes Parenteral routes

I.M S.C I.V I.D

Sublingual
 Drug Absorption
• Means movement of the drug from the • Routes by which drug molecules
site of administration to the systemic cross cell membranes
circulation across cell membrane
pH and Ionization

Clinical application:
 Acidic drugs absorbed
better in stomach while
basic drugs in intestine

 Acidic drugs excreted

faster in alkaline urine
whereas basic drugs in
acidic urine.
 Factors affecting drug absorption

Drug Factors Patient Factors

1. Lipid-solubility Vascularity and surface area of

the absorbing surface
2. pH & Degree of drug ionization Diseases

3. Pharmaceutical dosage form Functional integrity of

absorptive surface
4. Route of administration
 Bioavailability (F)
Plasma concentration-time curve (AUC)

• Defined as “ Fraction of a dose

of drug that is absorbed from
its site of administration and
reaches the systemic
circulation in an unchanged
form”
 Bioavailability
Plasma concentration-time curve (AUC) A drug given by i.v. will have an bio-
availability (100%) while drugs given
by other routes have <100 %

Factors affecting:
• Pharmaceutical factors ex. Dosage form,
lipid-solubility, route of administration
• Biological factors ex.Food, pH,ionization,
absorbing surface area, diseases
• First pass metaboilsm
 First Pass Metabolism

• Ex. High 1st pass effect

• Propranolol
• Morphine
 Drug Distribution & its Pattern

“Reversible transfer of a drug between

the blood & the extra-vascular fluids
& tissues of the body”

• Vascular system e.g: Dextran

• Uniformly distributed in body water
e.g: Ethanol
• Concentrated in tissues e.g: Iodine
 Plasma Protein Binding
• Acidic drugs - albumin(ex.NSAID ’s)
Basic drugs- acid glycoprotein(ex.Propranolol)

• Pharmacological significance: Prolongs the drug

availability & duration of action(reservoir)

• Drug displacement interactions :

Salicylates – tolbutamide: Hypoglycemia
Indomethacin - warfarin: Haemorrhage
 Apparent Volume of Distribution (aVd)

“Hypothetical volume of body • L o w a Vd e . g . Wa r fa r i n ( 8 L )

fluid into which a drug is • H i g h a Vd e . g . C h l o ro q u i n e
uniformly distributed at a ( 1 5 0 0 0 L )
concentration equal to that
in plasma” • Factors Affecting: Molecular size,
Lipid-solubility, Plasma protein &
aVd = Dose/Concentration (plasma) extra vascular protein binding,
disease states.
E.g: = 50mg/ 0.1mg = 500ml
• Clinical significance:
- In drug poisoning (hemodialysis)
- To calculate loading dose (drug)
 Biotransformation (Drug metabolism)

Biotransformation..?

“Enzyme catalyzed chemical

transformation of drugs from
nonpolar (lipid-soluble) to polar
(lipid-insoluble) compounds” so that
drug/metabolite is not reabsorbed
in renal tubules and are excreted.
 Sequential metabolism of a drug

DRUG
Unchanged
Phase I

Metabolite Phase II EXCRETION

Metabolite
EXCRETION

EXCRETION
 Drug Metabolizing Enzymes:
“Cytochrome P-450” (CYP -450)

• What are microsomal enzymes? Clinical implications:

• Which is the most abundant CYP
enzyme in the human liver?.
CYP3A4
• What are the pharmacological
significance of these enzymes?
 Enzyme induction – Rifampicin
with OCP – Unwanted pregnancy
 Enzyme inhibition: Cimetidine
with Dicumarol - Increases
bleeding
 Drug Excretion

• Process of removal of drugs from • Rate of elimination:

the systemic circulation into  GFR
extra corporeal fluids (e.g. urine  Plasma protein binding
or bile)
 Lipid solubility & ionization

• Major routes - Biliary or renal

• Minor routes - lung, skin, breast
milk
 Drug Excretion
Renal drug excretion Biliary drug excretion
 Plasma half Life (t1/2)

 It’s a time taken by the plasma

concentration of drug in the body to
be reduced by 50% of its original
value

 Half life determines:

 Duration of drug action
 To decide appropriate dosing
interval
 To estimate time required to
reach steady state in blood
 Drug Clearance (CL)

 It refers to the volume of blood  For drugs with first order kinetics,
cleared of the drug in unit time. clearance is constant

 Clearance values can provide useful

information about the biological fate
of a drug
 Rate and Pattern of Drug Elimination

• Rate of drug elimination is • Rate of drug elimination is

proportional to drug plasma independent of drug plasma
concentration concentration Ex. Ethanol
 Steady state Concentration

• Drug rate in = rate out are equal with a

dosing interval at every t1/2 (for 51/2
gives 97% )

• Pharmacological significance:
- Constant amount of drug in the body
- Patient will not experience neither
acute toxicity nor decline of drug effect.
- E.g. Digoxin, theophylline
ADME - Summary
Reference reader: Rang & Dale’s Text book of Pharmacology
 7th Edition- Chapter numbers 8,9 &10, page numbers 99-130.
 8th Edition- Chapter numbers 8,9 &10, page numbers 101-132.