1. Dr. Muslim Suardi, MSi., Apt.
METABOLISM
Dr. Muslim Suardi, MSi., Apt.
Faculty of Pharmacy
University of Andalas
2008

2. ELIMINATION
“The irreversible removal of drug from the body by all routes of elimination”
Metabolism
Excretion

3. Non Enzymatic (ester hydrolysis)
METABOLISM
Biotransformation
The process by which the drug is chemically converted in the body to a metabolite
Enzymatic
Non Enzymatic (ester hydrolysis)

4. Place of Metabolism Mainly: Liver Kidneys Lung Small Intestine Skin
GI mucosal cells
Microbiological flora in the distal portion of the ileum & large intestine

5. Metabolism in The Liver

6. 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)

7. 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

8. REACTIONS Phase I More polar metabolites A-synthetic reactions
Phase II
Conjugation
Synthetic reactions
Much more polar metabolites

9. 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

10. Phase I Oxidation Aromatic hydroxylation N-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

11. 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, & protein metabolism

12. 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

13. The rate constant of elimination (K) =
Hepatic Elimination
K = km + ke
The rate constant of elimination (K) =
first-order rate constant for metabolism (km) + the first-order rate constant for excretion (ke)

14. Clinical Focus
The overall el half life (t1/2) of a drug is 2 hr (K=0.3465/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 elimination route.

15. Clinical Focus K = km + ke, but ke = 0, thus k = km. T1/2 = 0.693/k.
= 6.7 hr

16. Variation of Biotransformation Enzymes in Humans
Genetics Factors
Environmental Factors
Drug Interactions
Physiologic Conditions
Drug Dosage Regimen

17. Genetics Factors Genetic different within population
Racial differences among different populations

18. Environmental Factors
Enzyme induction
Enzyme inhibition

19. Enzyme induction Enzyme inhibition
Drug Interactions
Enzyme induction Enzyme inhibition

20. Physiologic Conditions
Age
Gender
Diet/Nutrition
Pathophysiology

21. Drug Dosage Regimen Route of drug administration
Dose dependence (nonlinear) pharmacokinetics.

22. “Genetic differences in drug elimination “
Pharmacogenetics
“Genetic differences in drug elimination “
INH
N-acetylation
Rapid & slow acetylation
Slow acetylation neurotoxicity
The differences is referred to as genetic polymorphism.

23. Genetic Polymorphism Procainamide acetylated Hydralazin acetylated
Glucose-6-phosphate-dehydrogenase deficiency, approximately 10% of black Americans
Phenytoin, Efficient & Poor Metabolizer
Propranolol, difference among Chinese population

24. DI Involving Drug Metabolism
The enzymes involved in the metabolism of drugs may be altered by:
Diet
Co-administration of other drugs & chemicals

25. Enzyme Induction
A drug or chemical-stimulated increase in enzyme activity usually due to an increase in the amount of enzyme present
Eg.: Phenobarbital
Carbamazepine
Rifampicin
Benzopyren (Smoking)
Chlordane (Insecticide)

26. 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.
Eg.: Fluoxetine decrease the Cl of IMI due to its inhibitory effect of hydroxylation.

27. Inhibition Inhibitors Example Result PCT EtOH Increased hepatotoxicity
Cimetidine
Warfarin
Prolongation of prothrombin time
Erythromycin
Carbamazepine
Decreased Carbamazepine Cl

28. Induction Inducers of drug metabolism Example Result Carbamazepine PCT
Increased PCT metabolism
Rifampin
Methadone
Increased methadone metabolism

29. First Pass Metabolism

30. 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.

31. 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.

32. 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.