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1

Drug metabolism

  • Drug  metabolism is biochemical modification of pharmaceutical substances by living organisms usually through specialized enzymatic activity.
  • It converts lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted
  • Only water-soluble substances undergo excretion, whereas lipid soluble substances are passively reabsorbed from renal (kidney) or extra renal excretory sites back into the blood.

2

Effects of metabolism

Loss of pharmacological activity.

•Decrease in activity, with metabolites that show some activity.

•Increase in activity, more active metabolites.

•Activation of a prodrug (biologically inactive compound which can be metabolized in the body to produce a drug)

•Production of toxic metabolites.

-Direct toxicity

-Carcinogenesis. (the initiation of cancer formation.)

-Teratogenesis (defects in embryo/fetus) 

3

Enzymes

•Drug-metabolising Enzymes often have a wide substrate specificity, and individual drugs can be metabolised by more than one.

•Enzyme activity control is regulated at several levels.

•Some enzymes are expressed constitutively (regardless)

•Others are expressed or induced in the presence of a particular substrate.

 

4

Factors that afffect metabolism

Other drugs/herbals/natural substances

•Genetics

Hepatic blood flow

Liver disease

•Age

•Sex

•Ethnicity

Pregnancy

5

Enzyme induction

•Many of the important drug-metabolising enzymes can be induced by other compounds

Increased metabolism of drugs metabolised by that enzyme

•Resulting in decreased drug effect

•Induction of an enzyme involves increased synthesis and therefore increased activity.

•The most common enzyme inducers include alcohol and smoking.

•Many drugs and herbals such as phenytoin, carbamazepine, rifampicin and St John’s Wort can also induce metabolising enzymes.

•Process may take weeks

6

Enzyme inhibition

•Many commonly used drugs herbal medicines and food stuffs may conversely inhibit drug metabolising enzymes.

•Less metabolism occurs

•May be reversible or irreversible binding to the enzyme.

•Common culprits include: cimetidine, erythromycin, clarithromycin and ketoconazole, CCBs, grapefruit.

7

Genetic variation- Pharmacogenomics

•Wide variability in the response to drugs between individuals

•Consequences of such variation may be therapeutic failure or an adverse drug reaction

•Drug-metabolising enzymes are often expressed in multiple forms.

•Therefore inter-individual differences in gene expression are common.

•Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme.

•Genetic Polymorphisms

•Lack or decreased activity of an enzyme often results in increased drug toxicity.

•Less commonly there may be multiple expressions of a particular metabolising enzyme, which may result in enhanced metabolism and reduced drug effect or drug resistance.

•Eg – fast/slow acetylators; cholinesterase (suxamethonium).

 

8

Age- children 

•Drug-metabolising enzymes are often deficient or reduced in the fetus or premature infant.

Renal function is also deficient so drug and metabolites rapidly build up to toxic levels.

•By the age of two years children can metabolise many drugs more rapidly than adults.

•By puberty the rate of metabolism is greater than that of adults.

9

Gender

•Sex-based differences have been found in all four pharmacokinetic areas: Absorption, Distribution, Metabolism, and Elimination.

Responsiveness to certain drugs is different for men and women

Pregnancy – induction of certain drug-metabolizing enzymes occurs in second and third trimester

Hormonal changes during development have a profound effect on drug metabolism

 

10

Age (ederly)

•In the elderly parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism.

Chronic disease is also more common and so the elderly are likely to be on multiple drug therapy.

11

Ethnicity

Race may also affect drug metabolism.

•There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms.

12

Drug metabolism phases 

Phase 1:

  • oxidation
  • reduction
  • hydrolysis

Phase 2:

  • glucuronidation (xenobiotic metabolism) which leads to conjugation products.

Note:The cytochrome P-450 enzymes are the most important super family of metabolising enzymes.