PRINCIPLES OF PHARMACOKINETICS

KABWE COLLEGE OF HEALTH SCIENCES

PMH 125

Mr. R CHALWE
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Learning Objectives:

At the end of this module the student should be able to:

1. Describe the basic pharmacokinetic parameters
2. Apply the principles of pharmacokinetics to clinical situations
Outline
1. Pharmacokinetic Processes
2. Pharmacokinetic parameters
3. Pharmacokinetic variability
4. Clinical applications of pharmacokinetics
INTRODUCTION

Pharmacokinetics is the study of the time course of a drug and its metabolites in
the body after administration by any route.

Pharmacokinetics takes into account the processes of absorption distribution,

metabolism and excretion of drugs..

Pharmacokinetics makes it possible to model what may happen to a drug after it

has been administered to a patient.

Dosage regimens are determined from knowledge of the desired concentration-

time profile and pharmacokinetic parameters.
Pharmacokinetic Processes:
A. ABSORPTION

Absorption is the process of drug movement from the administration site to the
systematic circulation.

Drug absorption is determined by physico-chemical properties of drugs, their

formulations and routes of administration.
• Bioavailability
Bioavailability is the proportion of the administered drug dose that reaches the
system circulation in unchanged form and becomes available for
pharmacological effect
Bio-equivalence
The term ‘bio-equivalence’ refers to chemical equivalents that when
administered to the same person in the same dosage regimen results in
equivalent concentrations of drug in blood and tissues.
Chemical equivalence refers to drug products that contain the same compound in
the same amount and that meet current official standards; however, inactive
ingredients in drug products may differ.
B. DISTRIBUTION
After a drug enters the system circulation, it is distributed to the body’s tissues.
1 st phase: well perfused organs (e.g. liver, kidney, brain, etc);
2nd Phase: visceral sites (e.g. muscle, skin, fat, etc)
Factors affecting drug distribution

(i) Physicochemical factors (e.g. Drug lipophilicity)

(ii) Physiological factors (e.g. Cardiac output, regional
blood flow, capillary permeability, plasma proteins and
tissue volume/compartments)

Apparent volume of distribution

The volume of fluid into which a drug appears to be distributed is called apparent volume of distribution.

It is the fluid volume required to contain the drug in the body at the same concentration as in plasma.

The parameter provides a reference for the plasma concentration expected for a given dose and for the dose
required to produce a given concentration.
Drug binding to proteins and tissues
The extent of drug distribution into tissue depends on the extent of
plasma protein and tissue binding.

Plasma protein binding

Drugs are transported in the blood stream partly in solution as free (unbound)
drug and partly bound to blood components (e.g. plasma proteins & blood cells)
The most important plasma proteins that can bind dugs are:
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2.Alpha1 acid glycoprotein
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Acidic drugs are generally bound more extensively to albumin and basic drugs to
alpha1 acid glycoprotein and/or lipoprotein.

It is the unbound drug concentration that is more closely related to drug
concentration at the active site and to drug effects.

Relationship between binding and apparent volume of distribution

Drugs that are highly bound on plasma proteins have low volumes of distribution
while those that are extensively bound on tissues have high volumes of
distribution.
C. ELIMINATION
Elimination is the sum of the processes of drug loss (metabolism and excretion) from the body.
Metabolism
The liver is the principal site of drug metabolism. Other sites are the kidney, skin and lungs.
Drug metabolism occurs in two phases:
1. Phase I metabolism: involves chemical alteration of the basic structure of the drug e.g. oxidation,
reduction or hydrolysis.
• Converts parent drug to more polar metabolite which is excreted or becomes liable to subsequent
conjugation (phase II) reactions
2. Phase II metabolism: involves conjugation e.g. sulphation, glucuronidation, methylation or
acetylation.
Conjugation reaction of Phase I metabolites with endogenous substance to form highly polar rapidly
eliminated conjugates;
Cytochrome P-450
The most important enzyme system of phase I metabolism is cytochrome P-450.

The most important cytochrome P450 enzymes in human metabolism are

CYP1A2, CYP2CP, CYP2C19, CYP2D6 and CYP3A4.

Excretion

This is the process by which a drug or its metabolite is eliminated from the body
without further chemical change.

The kidney is the main route whereby drugs are excreted from the body.
Renal excretion
Renal excretion of drugs occurs chiefly by the following three
processes:
1. Glomerular filtration
2. Passive tubular reabsorption
3. Active tubular secretion
• Total renal clearance = clearance by filtration plus clearance by
secretion minus retention by reabsorption.
PHARMACOKINETIC PARAMETERS

Clearance (Cl)
The volume of fluid (usually serum, plasma or blood) that is completely cleared
of drug per unit time.
Clearance = rate of drug elimination /plasma drug concentration
The units of clearance are volume/time e.g. L/hr or ml/min
Clearance determines the average concentration achieved if drug is administered
at regular intervals.
Volume of distribution (Vd)
Volume of distribution is the amount of fluid that would be required to contain
the drug in the body at the same concentration as in the blood or plasma.
Vd = amount of drug in body/plasma drug concentration
Elimination rate constant (ke)
This is a function of how a drug is cleared from the blood by the eliminating
organs and how the drug distributes throughout the body.
Ke = rate of drug elimination/amount of drug in body = Cl/Vd

Elimination half-life (t½)

The time required for the plasma drug concentration or the amount of drug in
the body to decrease by 50%.
t½ = natural log (ln) 2/ke
PHARMACOKINETIC VARIABILITY

The dose required to produce a certain response may vary widely from individual
to individual. Two sources of this variability are:

1. Differences in blood levels at the site of action produced by a given dose

2. Differences in effect produced by a given drug concentration.

For many drugs the principal variation is the drug concentration resulting form
given doses (pharmacokinetic variability).
Factors that contribute to pharmacokinetic variability
• Factors that may affect the completeness of absorption
• Age
• Weight
• Genetic factors
• Environmental factors
• Diseases
• Drug interactions
1. AGE
For neonates and infants, renal and hepatic functions are not fully
developed. In addition concentrations of albumin and alpha-1-acid
glycoprotein are low in neonates.
From the age of 20 years, renal function decreases about 1% per year.
Aging also results in decrease in liver size, and hepatic blood flow, and in the
activity of hepatic drug metabolizing enzymes.
Dosing of drugs should therefore take note of the effects of extremes of age
in the pharmacokinetics of various drugs.
Body composition changes with age. Fat contributes a greater proportion to
body mass in the elderly, while neonates have a lower proportion of adipose
tissue.
Neonates therefore have a reduced relative volume of distribution while
elderly people have increased volume of distribution for lipid soluble drugs.
2. WEIGHT

 Drug clearance and volume of distribution are related to body weight.

 For some drugs lean body mass, ideal body weight and body surface area are
better predictors of volume of distribution and clearance.

3. PREGNANCY
Rate of oral absorption is reduced in late pregnancy.
Concentration of plasma proteins falls during pregnancy and drug binding is
reduced.
Maternal plasma volume increases.
Glomerular filtration rate and creatinine clearance are increased in pregnancy.
Metabolism of anti-convulsants (e.g. phenyloin, phenobarbital and
carbamazepine) is increased.
4. GENETIC FACTORS & ETHNICAL DIFFERENCES
Genetic polymorphism: there are genetically determined differences in the ability of individuals
to metabolism certain drugs.
Genetic polymorphism has been demonstrated for both cytochrome P450 enzymes (e.g.
CYP2D6, CYP2C10, CYP2C9 & CYP1A2) and non-cytochrome P450 enzymes (e.g. N-
acetyltransferase, pseudo-cholinesterase and alcohol dehydrogenase).
There are ethnical differences in N-acetyltransferase and alcohol dehydrogenase activities.
5. ENVIRONMENTAL FACTORS
Ethanol: Acute ethanol intoxication inhibits hepatic drug metabolism while chronic alcohol
intake stimulates drug metabolism.
Chronic alcohol intake may lead to liver cirrhosis with resultant reduction in hepatic
metabolism.
Tobacco smoke contains polycyclic aromatic hydrocarbons that are potent inducers of certain
drug metabolizing enzymes. Chronic smoking increases metabolism of theophylline,
propranolol and imipramine.
Diet: Certain vegetables (e.g. cabbage, cauliflower and broccoli) induce aryl hydrocarbon
hydroxylase. Charcoal broiled beef enhances drug metabolism.
6. DISEASE

A. Renal Function Impairment

Renal failure may change the volume of distribution e.g. decrease in digoxin volume of
distribution (due to decreased tissue binding) and increase in phenytoin volume (due to
decreased albumin binding).
Metabolism of drugs that are metabolized by the kidneys (e.g. insulin) is reduced in patients
with renal failure.
Total clearance is reduced in renal impairment for those drugs that are renally excreted
unchanged.
B. Hepatic Disease
Hepatic dysfunction reduces metabolic clearance of drugs.
First-pass metabolism may decrease and thus oral bioavailability may increase e.g. oral
bioavailability of morphine and nifedipine is almost doubled in patients with liver cirrhosis.
 Liver cirrhosis often results in reduced plasma protein binding because of lowered plasma
albumin.
C. Heart Failure and Shock
Decreased blood flow to the kidney and liver impairs drug clearance.
D. Physiologic Stress
The concentration of alpha1 - acid glycoprotein increases during physiologic stress (e.g.
myocardial infarction and surgery). Therefore binding of some drugs (e.g. propranolol and
quinidine) to alpha1 - acid glycoprotein increases with resultant decrease in their volumes
of distribution.
E. Thyroid Disease
 Volume of distribution of some drugs is increased in hyperthyroidism and reduced in
hypothyroidism (e.g. digoxin)
 Metabolism of some drugs is increased in hyperthyroidism and reduced in hypothyroidism
(e.g. propranolol)
 Renal elimination of some drugs is increased in hyperthyroidism and reduced in
hypothyroidism (e.g. digoxin).
[Link] INTERACTIONS

Pharmacokinetic interactions are mainly due to alteration of drug absorption,

distribution, metabolism or excretion.
A. Drug Absorption
Binding or chelation of drugs in the GIT e.g. alumimium containing antacids and
ferrous sulphate reduce absorption of tetracyclines.
Altered GIT motility e.g. anticholinergic drugs decrease GI motility and may
reduce absorption by slowing gastric emptying.
Altered pH e.g. drugs that increase gastric pH (e.g. cimetidine) decrease the
solubility of certain drugs (e.g. ketoconazole) and impair their absorption.
Effect of food: Food may delay or reduce the absorption of many drugs (e.g.
didanosine). However the absorption of some drugs ([Link]-
lumefantrine) is enhanced by food intake.
B. Distribution
Drugs may be displaced from plasma protein binding sites when two protein-bound drugs are
given concurrently (competitive displacement). However most of these interactions do not
have clinical significance because there is an increase in clearance of the displaced drug.
Displacement reactions where there is an additional interaction are clinically important e.g.
sodium valproate can cause phenytoin toxicity because it displaces phenytoin from its binding
site on plasma albumin and inhibits its metabolism.
C. Metabolism
Stimulated metabolism: One drug may increase the activity of hepatic enzymes (enzyme
induction) involved inn the metabolism of another drug e.g. phenobarbital increases the
metabolism of warfarin and steroid hormones. Other enzyme inducers include carbamazepine,
phenytoin and rifampicin.
Inhibited metabolism: one drug may inhibit the metabolism of another e.g. cimetidine inhibits
cytochrome P450 enzymes and this inhibits the metabolism of drugs such as theophylline and
warfarin. Other inhibitors of cyctochrome p450 enzymes include erythromycin, ketoconazole,
ritonavir and ciprofloxacin.
D. Renal Excretion
Altered urinary pH: urinary pH influences the ionization of weak acids and bases,
thus affecting their re-absorption and excretion.
A drug that raises urinary pH (e.g. sodium bicarbonate) will increase the excretion
of weak acids (e.g. aspirin) while one that lowers urinary pH (e.g. ammonium
chloride) will increase the excretion of weak bases (e.g. amphetamine).
Altered active transport: One drug may interfere (competitively or non-
competitively) with active tubular re-absorption or tubular secretion of another
drug e.g. probenecid blocks the tubular secretion of penicillins and the active re-
absorption of uric acid; NSAIDS inhibits active tubular secretion of methotrexate.
ANY QUESTION