A 52-year-old man with hypertension is started on enalapril. After 2 weeks, he develops a persistent dry cough. Which of the following is the most common site of drug metabolism for ACE inhibitors?

Explanation

## Metabolism of ACE Inhibitors **Key Point:** Most ACE inhibitors are prodrugs (e.g., enalapril, ramipril, lisinopril) that undergo hepatic hydrolysis by esterases to yield their active diacid forms. The **liver** is therefore the primary site of drug metabolism for ACE inhibitors. ### Sites of Drug Metabolism — ACE Inhibitors | Site | Mechanism | Clinical Relevance | | --- | --- | --- | | **Liver** | Hepatic esterases hydrolyze prodrug (e.g., enalapril → enalaprilat) | **Primary site of metabolism**; impaired in severe hepatic disease | | Kidney | Glomerular filtration; primary route of **elimination** of active metabolite | Dose reduction needed in renal failure, but this is excretion, not metabolism | | Lungs | ACE present in pulmonary endothelium; bradykinin accumulation causes cough | Site of **pharmacological action/adverse effect**, not metabolism | | Intestine | Minimal first-pass hydrolysis | Not the primary metabolic site | ### Why Liver is the Answer **High-Yield:** Enalapril is a classic example of a prodrug ACE inhibitor. After oral absorption, it is hydrolyzed by **hepatic esterases** to its active form, **enalaprilat**. This hepatic biotransformation is the primary metabolic step. The active metabolite is subsequently eliminated by the kidneys (renal excretion), but metabolism itself occurs in the liver. This distinction — metabolism vs. elimination — is a classic NEET PG exam trap. **Clinical Pearl:** The dry cough in this patient is caused by **bradykinin accumulation** in the pulmonary vasculature (lungs), where ACE normally degrades bradykinin. Inhibition of ACE leads to bradykinin build-up, stimulating cough receptors. This is a pharmacodynamic adverse effect, entirely separate from the pharmacokinetic question of where the drug is metabolized. **Reference:** KD Tripathi, *Essentials of Medical Pharmacology*, 8th ed., Chapter on Antihypertensives — ACE inhibitors are described as prodrugs activated by hepatic esterases. **Mnemonic:** **HELP** — **H**epatic **E**sterases **L**iberate the **P**harmacologically active form of ACE inhibitor prodrugs.