2.3 Metabolism
Drug metabolism (biotransformation) converts drugs to more polar metabolites for excretion. The liver is the primary site via cytochrome P450 enzymes.
Phase I Reactions
Introduce or expose functional groups. Often create reactive metabolites.
Oxidation (CYP450)
Most common. CYP3A4 metabolizes ~50% of drugs. CYP2D6, CYP2C9, CYP2C19 also major.
Reduction
Ketone → alcohol, nitro → amine. CYP450, aldo-keto reductases.
Hydrolysis
Esters, amides cleaved. Esterases, amidases. Prodrug activation.
Phase II Reactions (Conjugation)
Attach polar groups to increase water solubility for excretion.
Glucuronidation
UGT enzymes. Most common. Morphine, bilirubin, steroids.
Sulfation
SULT enzymes. Phenols, steroids. Limited capacity.
Glutathione Conjugation
GST enzymes. Detoxifies reactive metabolites. Acetaminophen toxicity.
Acetylation
NAT enzymes. Isoniazid, sulfonamides. Slow/fast acetylator polymorphism.
Major CYP450 Enzymes
| Enzyme | % Drugs | Examples | Polymorphism |
|---|---|---|---|
| CYP3A4 | ~50% | Statins, cyclosporine, HIV PIs | Low |
| CYP2D6 | ~25% | Codeine, tamoxifen, metoprolol | High (PM 5-10%) |
| CYP2C9 | ~15% | Warfarin, phenytoin, NSAIDs | Moderate |
| CYP2C19 | ~10% | Clopidogrel, omeprazole | High |
Enzyme Induction & Inhibition
Inducers
Increase enzyme expression (days to weeks)
Rifampin, phenytoin, St. John's wort, carbamazepine
Inhibitors
Block enzyme activity (immediate)
Ketoconazole, erythromycin, grapefruit juice, ritonavir