Which is the commonest site of drug metabolism in the body?

Explanation

## Site of Drug Metabolism **Key Point:** The liver is the primary organ responsible for drug metabolism, accounting for approximately 75–80% of all Phase I and Phase II metabolic reactions in the body. ### Why the Liver Dominates 1. **Enzyme richness**: The hepatic microsomes contain the highest concentration of cytochrome P450 (CYP) enzymes, particularly CYP3A4, CYP2D6, and CYP2C9. 2. **First-pass metabolism**: Drugs absorbed from the GI tract enter the portal circulation and undergo hepatic metabolism before reaching systemic circulation. 3. **Phase II capacity**: The liver also houses the majority of conjugation enzymes (UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases). ### Comparative Contribution of Other Sites | Site | Contribution | Key Enzymes | Clinical Relevance | |------|--------------|-------------|--------------------| | **Liver** | 75–80% | CYP450, UGT, COMT, MAO | First-pass effect, drug–drug interactions | | **Kidney** | 10–15% | Amine oxidases, peptidases | Renal clearance; active secretion | | **Lungs** | 5–10% | CYP2E1, MAO | Volatile anesthetic metabolism | | **GI mucosa** | 5% | CYP3A4, UGT | First-pass metabolism; P-gp efflux | | **Blood/Plasma** | <5% | Esterases, pseudocholinesterase | Rapid hydrolysis of esters | **High-Yield:** Hepatic impairment (cirrhosis, hepatitis) significantly reduces drug clearance and increases the risk of drug toxicity. Dose adjustments are mandatory for hepatically metabolized drugs in liver disease. **Clinical Pearl:** Drugs that undergo extensive first-pass hepatic metabolism (e.g., propranolol, nitroglycerin, morphine) show poor oral bioavailability and require either higher oral doses or alternative routes (sublingual, transdermal, IV) to achieve therapeutic levels. **Mnemonic:** **HURL** — Hepatic metabolism is the main route; Urinary excretion is secondary; Renal metabolism is minor; Lung metabolism is least.