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Flashcards in Drug metabolism Deck (22):

What is drug metabolism?

- Biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity
- Essential pharmacokinetic process that limits life of a substance in the body rending lipid soluble and non-polar compounds to water soluble and polar compounds so they can be excreted


What do drugs have to become polar or water soluble

so they can be excreted. Can't do it if they're lipid soluble or non-polar


Site of metabolism

- Important sites: liver, lining of gut, kidneys and lungs
- Metabolised by enzymes: drugs can often be metabolised by more than one enzyme due to number of active sites
- Some enzymes are expressed constitutively and others are induced in the presence of a particular substrate



- Increase water solubility and aid excretion
- Deactivate compounds



- Activate following metabolism or form active metabolites e.g. codeine, enalapril


Effects of metabolism

- Loss of pharmacological activity
- Decrease in activity, with metabolites that show some activity
- Increase activity -> prodrug
- Production of toxic metabolites: direct toxicity, carcinogenesis, teratogenesis


Phases of metabolism

- Phase 1: oxidation, reduction, hydrolysis
- Phase 2: conjugation


Phase 1 of metabolism

- Oxidation
- Hydrolysis
- Increases the polarity of the compound and provides an active site for phase 2 metabolism
- Cytochrome P-450 enzymes is most important super family of metabolising enzymes


Cytochrome P-450 isoforms

- CYP3A4 is major constitutive enzyme in human liver, contributes to wide range of drugs, also found in gut
- CYP2D6
- CYP1A2



- in liver and also in gut
- Drugs: diazepam, methadone, simvastatin, CCBs



- Metabolism for some antidepressants, antipsychotics and conversion of codeine to morphine
- Reduced or absent expression is found in 5-10%
- Can also be induced by smoking



- Induced by smoking, need a higher dose for many antidepressants


Phase 2

- Conjugation: increases water solubility and enhances excretion of metabolised compound
- Involves attachment of glucaronic acid, glutahione, sulphate or acetate to metabolite generated by Phase 1
- Endogenous molecule donates a portion of itslef to the foreign molecule


Factors that affect metabolism

- Other drugs/herbals/natural substances
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy


Examples of interfering herbals/natural substances

- St John's Wort
- Grapefruit
- Herbals often have active compounds


Genetic factors affecting metabolism

- Can lead to therapeutic failure or adverse drug reaction
- Pharmacokinetic and pharmadynamic responses can change
- Drug-metabolising enzymes are expressed in multiple forms -> inter-individual difference
- Genetic polymorphism


Genetic polymorphism affecting metabolism

- Gene mutations resulting in absence or deficiency of particular metabolising enzyme. Can lead to increasing drug toxicity
- Can increase expressions of particular metabolising enzymes. Enhanced metabolism, reduced effect
- CYP2D6 polymorphism: poor metabolisers, intermediate metabolisers, extensive metabolisers, ultrarapid metabolisers. Wafarin, pheytoin


Children: drug metabolism

- Children: metabolising enzymes can often be deficient or reduced in foetus or premmys
- Renal function is also deficient, metabolites build up to toxic levels
- However, 2yo can metabolise quicker than adults and it slows again in puberty


Elderly: drug metabolism

- Plasma protein, lean body mass and liver mass all decrease significantly and alter drug metabolism
- Chronic disease is more common -> multiple drug therapy. High risk individual



- Differs between men and women
- Pregnancy: hormonal changes have profound effect on drug metabolism


Enzyme induction:

- Many drug metabolising enzymes can be induced by other compounds
- Resulting in increased metabolism of drug and decreased drug effect
- Most common enzyme inducers include alcohol and smoking
- Process may take weeks or months to happen


Enzyme inhibition

- Many commonly used drugs, herbal medicines and foodstuffs can inhibit enzymes: reversible or irreversible binding to the enzyme
- Inhibition can take immediate effect