PHARMACOKINETICS- apt. Uswatul Hasanah, M.

Si
METABOLISM
LEARNING OBJECTIVES
Upon completion of this topic, you should be able to:
Describe metabolism process in pharmacokinetics
Define the concept of drug clearance
DEFINITION
Elimination

Irreversible removal of drug from the body

Metabolism/Biotransformation

Enzymatic

Non enzymatic (ester hydrolysis)

Excretion
 Place of metabolism

Liv Kid Lun Small Ski

Microbia
GI flora in
intesti mucos distal ileum

er neys g ne n al cells
and large
intestine
CLEARANCE

“The process of drug elimination from the body or from the single organ without identifying the
individual processes involved”

The volume of fluid cleared of drug from the body per unit of time (mL/min)
BIOTRANSFORMATION
REACTION
Active drug to inactive
metabolite
•Amphetamine  phenylacetone
Active drug to active
metabolite
•Codeine  morphine
Inactive drug to active
metabolite
•Hetacilin  ampicilin
Active drug to reactive •Paracetamol  reactive metabolite pBQ & NAPQI
intermediate
 DRUGS WITH ACTIVE
METABOLITES
Drug Metabolite Pharmacological
activity
Procainamide N acetyl procainamide Anti-dysrhytmic
Propranolol HCl 4-hydroxypro- non-selective
pranolol ß-antagonist
Diazepam desmethyldiazepam Symptomatic relief of
tension and anxiety
REACTION PHASE

Phase II
Phase I
• Conjugation
• More polar
Metabolism • Synthetic reactions
metabolites
• Much more polar
• A synthetic reactios
metabolites
PHASE I Oxidation Reduction Hydrolysis

Aromatic
hydroxylation
Occurs first Azoreduction
Side chain Ester
hydroxylation hydrolysis
Introduce or expose a functional group on drug
mol N-, O-, and S-
dealkylation Nitroreductio
Oxygen into phenyl group of phenylbutazone by n
aromatic hydroxylation to form oxyphenbutazone Deamination

Sulfooxidation, Amide
Codeine is demethylated to form morphine N-oxidation Alcohol hydrolysis
dehydrogenas
N-hydroxylation e
Hydrolysis of ester Aspirin to form Salicylic
Acid
PHASE II

Glucoronid
Sulfation
ation

Amino acid
Acetylation
ELIMINATION RATE
CONSTANT (K)

K = km + ke

• Overall half life of a drug is 2 hr, and metabolism rate constant is 0.104/hr
• In the case of certain kidney disorder  less or non of drug will be excreted by renal, and hepatic metabolism is the only
way to eliminate drug  longer half life

Example:
 VARIATION OF
BIOTRANSFORMATION
ENZYMES IN HUMANS
•Racial •Enzyme induction •Enzyme indu
•population •Enzyme inhibitor •Enzyme inhib
Genetics Factors Environmental Factors Drug Interactions

•Age
•Route of drug administration
•Gender
•Dose dependence (nonlinear)
•Diet/Nutrition
•Pathophysiology pharmacokinetics.

Physiologic Conditions Drug Dosage Regimen

GENETIC POLYMORPHISM

Glucose-6-phosphate-dehydrogenase deficiency

• approximately 10% of black Americans

Propranolol

• difference among Chinese population (CYP2D6 genotypes)

Phenytoin

• CYP2C9 genotype in various ethnicity

 Inhibitors Example Result

DRUG INTERACTION Paracetamol etOH Increased

hepatotoxicity
Cimetidine Warfarin Prolongation of
prothrombin time
Diet, other drugs & chemicals Erythromycin Carbamazepine Decreased
carbamazepine
Enzyme induction : increase in the Clearance
amount of enzyme present
Enzyme inhibitor : substrate competition
Inducer Example Result
or direct inhibition of drug metabolizing
enzyme Carbamazepine Paracetamol Increased PCT
metabolism
Rifampin Methadone Increased
methadone
metabolism
FIRST PASS EFFECT
Routes of administration:

• Distribute within the body prior to liver metabolism

• Parenteral
• Transdermal
• Inhalation
• Absorbed in duodenal segment, and transported to hepatic portal vein
• Oral

Affect the bioavailability for drugs that highly metabolized by liver