Which of the following enzyme systems is primarily responsible for the metabolism of warfarin, making it susceptible to numerous drug interactions?

Explanation

## Warfarin Metabolism and Drug Interactions **Key Point:** Warfarin is metabolized primarily by CYP2C9, making it one of the most drug-interaction-prone anticoagulants in clinical practice. ### Mechanism Warfarin is a racemic mixture of S- and R-enantiomers. The S-enantiomer (more potent) is metabolized by CYP2C9, while the R-enantiomer undergoes metabolism via CYP1A2 and CYP3A4. However, CYP2C9 is the dominant pathway and the primary site of clinically significant interactions. ### Clinical Significance | Interaction Type | Examples | Effect | |---|---|---| | CYP2C9 Inhibitors | NSAIDs, fluconazole, amiodarone, sulfamethoxazole | ↑ Warfarin levels → bleeding risk | | CYP2C9 Inducers | Rifampicin, phenytoin, carbamazepine | ↓ Warfarin levels → thrombosis risk | | Protein Binding Displacement | Aspirin, NSAIDs, sulfonamides | ↑ Free warfarin → enhanced effect | **High-Yield:** CYP2C9 polymorphisms (CYP2C9*2, *3 variants) also affect warfarin metabolism, explaining variable individual responses and the rationale for pharmacogenetic-guided dosing. **Clinical Pearl:** Patients on warfarin require INR monitoring when any new drug is added or removed, especially those metabolized by or affecting CYP2C9. ### Why Other Options Are Incorrect - **CYP3A4:** While important for many drugs, it plays a secondary role in warfarin metabolism - **Monoamine oxidase:** Not involved in warfarin metabolism; relevant for tyramine and certain antidepressants - **Catechol-O-methyltransferase:** Metabolizes catecholamines and levodopa, not warfarin