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

Question

Accepted Answer

D. Liver. ## 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.

Answer

A. Kidney

Answer

B. Intestinal mucosa

Answer

C. Lungs

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

Explanation

Site of Drug Metabolism

Why the Liver Dominates

Comparative Contribution of Other Sites

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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