Which of the following mechanisms best explains the pharmacokinetic interaction between rifampicin and warfarin, resulting in decreased anticoagulant effect?

Explanation

## Mechanism of Rifampicin-Warfarin Interaction **Key Point:** Rifampicin is a potent inducer of the hepatic cytochrome P450 enzyme system, particularly CYP2C9, which is responsible for the metabolism of warfarin (S-enantiomer). ### How Enzyme Induction Works Rifampicin increases the expression of CYP2C9 by acting as a ligand for the pregnane X receptor (PXR), leading to: 1. Increased hepatic metabolism of warfarin 2. Reduced plasma concentration of warfarin 3. Decreased anticoagulant effect (INR reduction) **High-Yield:** Rifampicin is one of the most potent broad-spectrum enzyme inducers in clinical practice. It induces CYP3A4, CYP2C9, CYP2C19, and CYP2B6. ### Clinical Consequence Patients on warfarin who start rifampicin require: - Increased warfarin dosing (often 2–3 fold) - More frequent INR monitoring - Dose adjustment when rifampicin is discontinued (to avoid over-anticoagulation) **Clinical Pearl:** The interaction becomes clinically apparent within 5–7 days of starting rifampicin, as enzyme induction reaches steady state. ### Other Notable CYP2C9 Inducers | Inducer | Target Enzymes | Clinical Significance | |---------|---|---| | Rifampicin | CYP3A4, CYP2C9, CYP2C19 | Most potent; broad spectrum | | Phenytoin | CYP3A4, CYP2C9, CYP2C19 | Moderate; long half-life | | Carbamazepine | CYP3A4, CYP2C9 | Moderate; auto-induction | | Phenobarbital | CYP3A4, CYP2C9, CYP2C19 | Moderate; long-acting | **Mnemonic:** **PC BRAS** — Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Alcohol (chronic), St. John's wort — all induce CYP450 enzymes.