METABOLISM

Deswien, Apt
School of Pharmacy
Faculty of Sciences, University of Andalas
 ELIMINATION

The irreversible removal of drug from the

body by all routes of elimination
• Metabolism
• Excretion
 METABOLISM
Biotransformation
The process by which the drug is chemically
converted in the body to a metabolite

• Enzymatic
• Non Enzymatic (ester hydrolysis)
 Location of Metabolism
• Mainly: Liver
• Kidney
• Lung
• Small Intestine
• Skin
• GI mucosal cells
• Microbiological flora in the distal portion of
the ileum & 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
REACTIONS
• Active drug to inactive metabolite
Amphetamine Phenylacetone

• Active drug to active metabolite

Codeine Morphine

• Inactive drug to active metabolite

Hetacillin Ampicllin

• Active drug to reactive intermediate

PCT Reactive metabolite
 REACTIONS
• Phase I
More polar metabolites
A-synthetic reactions
• Phase II
Conjugation
Synthetic reactions
Much more polar metabolites
 Phase I
• Occurs first
• Introduce or expose a functional group on
drug mol
• Oxygen into phenyl group of
phenylbutazone by aromatic hydroxylation
to form oxyphenbutazone
• Codeine is demethylated to form morphine
• Hydrolysis of ester Aspirin to form Salicylic
Acid
 Phase I
• Oxidation Aromatic hydroxylation
Side chain hydroxylation
N-, O-, and S-dealkylation
Deamination
Sulfooxidation, N-oxidation
N-hydroxylation
• Reduction Azoreduction
Nitroreduction
Alcohol dehydrogenase
• Hydrolysis Ester hydrolysis
Amide hydrolysis
 Phase II
• Salicylic Acid with glycine to form
salicyluric acid
• Salicylic Acid with glucoronic acid to form
salicylglucoronide
• Conjugating reagents
• Derived from biochemical compounds
involved carbohydrate, fat, and protein
metabolism
 Phase II
• Glucuronidation by Glucuronic acid
• Sulfation by Sulfate
• Amino acid conj by Glycine
• Acetylation by Acetyl CoA
• Methylation by CH3
• Glutathione conj by glutathione
 Hepatic Elimination
• K = km + ke
• The rate constant of elimination (k) = first-
order rate constatn for metabolism (km) +
the first-order rate constant for excretion
(ke)
 Clinical Focus
• The overall el half life (t1/2) of a drug is 2
hr (k=0.347/hr, km=0.104/hr. If the renal
excretion pathway becomes impaired as in
the case of certain kidney disorders, then
less or none drug will be excreted renally
& hepatic metabolism may become the
primary drug el route.
• K = km + ke, but ke = 0, thus k = km.
• T1/2 = 0.693/k. t1/2 = 0.693/0.104= 6.7 hr
 Variation of Biotransformation
Enzymes in Humans
• Genetics Factors
• Environmental Factors & Drug Interactions
• Physiologic Conditions
• Drug Dosage Regimen
 Genetics Factors
• Genetic different within population
• Racial differences among different
populations
Environmental Factors & Drug
Interactions

Enzyme induction
Enzyme inhibition
Physiologic Conditions

Age
Gender
Diet/Nutrition
Pathophysiology
Drug Dosage Regimen

Route of drug administration

Dose dependence (nonlinear)
pharmacokinetics.
 Pharmacogenetics
“Genetic differences in drug elimination “
• INH
• N-acetylation
• Rapid & slow acetylation
• Slow acetylation neurotoxicity
• The differences is referred to as genetic
polymorphism.
 Genetic Polymorphism
• Procainamide acetylated
• Hydralazin acetylated
• Glucose-6-phosphate-dehydrogenase
deficiency, which is observed in
approximately 10% of black Americans
• Phenytoin, EM & PM (Efficient & Poor
Metabolizer)
• Propranolol, difference among Chinese
population
 Drug Interactions Involving Drug
Metabolism

The enzymes involved in the metabolism

of drugs may be altered by:
• Diet
• Co-administration of other drugs &
chemicals
 Enzyme induction
A drug or chemical-stimulated increase in
enzyme activity usually due to an increase
in the amount of enzyme present
• Examples: Phenobarbital
Carbamazepine
Rifampicin
Benzopyren (Smoking)
Chlordane (Insecticide)
 Enzyme Inhibition
• May be due to substrate competition or
due to direct inhibition of drug
metabolizing enzyme, particularly one of
several of the cytochrome P-450 enzymes.
• Examples: Fluoxetine decrease the
clearance of IMI due to its inhibitory effect
of hydroxylation.
 Inhibition
Inhibitors Example Result

PCT EtOH Increased

hepatotoxicity
Cimetidine Warfarin Prolongation of
prothrombin
time
Erythromycin Carbamazepine Decreased
Carbamazepine
clearance
 Induction
Inducers of Example Result
drug
metabolism
Carbamazepine PCT Increased PCT
metabolism
Rifampin Methadone Increased
methadone
metabolism
 First Pass Effect
• Routes of administration may affects the
metabolic rate

• A drug given parenterally, transdermally,

or by inhalation may distribute within the
body prior to metabolism by the liver.
 First Pass Effect
• In contrast, drugs given orally are normally
absorbed in the duodenal segment of the
small intestine and transported via the
mesenteric vessels to the hepatic portal
vein & then to the liver prior to the
systemic circulation.
 First Pass Effect
• Drugs that are highly metabolized by the
liver or by the intestinal mucosal cells
demonstrate poor systemic availability
when given orally.
• This rapid metabolism of an orally
administered drug prior to reaching the
general circulation is termed FPE or pre-
systemic elimination.