Hepatic Drug Metabolism
How the liver transforms drugs through Phase I and Phase II reactions, and the role of cytochrome P450 enzymes.
The Liver as Drug-Processing Center
The liver is the primary site of drug metabolism, converting lipophilic parent compounds into more hydrophilic metabolites that the kidneys can excrete. Hepatocytes contain the enzymatic machinery — concentrated in the smooth endoplasmic reticulum — that performs these biotransformations.
Phase I Reactions (Functionalization)
Phase I reactions introduce or expose a functional group (-OH, -NH2, -SH) through oxidation, reduction, or hydrolysis. The cytochrome P450 (CYP) enzyme superfamily catalyzes most Phase I oxidations.
Key CYP Enzymes
| Enzyme | % of Drug Metabolism | Notable Substrates |
|---|---|---|
| CYP3A4 | ~50% | Statins, cyclosporine, midazolam |
| CYP2D6 | ~25% | Codeine, metoprolol, fluoxetine |
| CYP2C9 | ~15% | Warfarin, phenytoin, NSAIDs |
| CYP2C19 | ~5% | Omeprazole, clopidogrel |
| CYP1A2 | ~5% | Theophylline, caffeine, clozapine |
Phase I metabolites may be pharmacologically active (e.g., morphine from codeine via CYP2D6), inactive, or even toxic (e.g., NAPQI from acetaminophen via CYP2E1).
Phase II Reactions (Conjugation)
Phase II reactions attach a polar endogenous molecule to the drug or its Phase I metabolite, greatly increasing water solubility. Major conjugation pathways include:
- Glucuronidation (UGT enzymes): the most common pathway; conjugates morphine, bilirubin, NSAIDs
- Sulfation (SULTs): acetaminophen, steroids, thyroid hormones
- Acetylation (NAT1/NAT2): isoniazid, hydralazine, sulfonamides
- Glutathione conjugation (GSTs): detoxifies reactive Phase I metabolites like NAPQI
- Methylation (COMTs, TMTs): catecholamines, mercaptopurine
Enzyme Induction and Inhibition
- Inducers (rifampin, phenytoin, carbamazepine) upregulate CYP expression over days to weeks, increasing metabolism of co-administered drugs and reducing their efficacy.
- Inhibitors (ketoconazole, erythromycin, grapefruit juice) block CYP activity rapidly, increasing plasma levels and toxicity risk of substrates.
Genetic Polymorphisms
CYP2D6 polymorphisms classify individuals as poor, intermediate, extensive, or ultra-rapid metabolizers. Poor metabolizers of codeine get no analgesic effect (no morphine formed); ultra-rapid metabolizers risk opioid toxicity.
Key Takeaways
- Phase I (CYP450) adds functional groups; Phase II conjugates polar molecules
- CYP3A4 and CYP2D6 together handle approximately 75% of drug metabolism
- Enzyme inducers decrease and inhibitors increase substrate drug levels
- Genetic polymorphisms in CYP enzymes cause predictable interindividual variability