An enzyme inducer such as rifampicin reduces plasma concentrations of concurrently administered drugs by which mechanism?

• A Competing for protein binding sites, increasing free drug fraction and renal clearance
• B Activating the pregnane X receptor (PXR), which transcriptionally upregulates CYP450 enzymes (CYP3A4, CYP2C9) and P-glycoprotein, increasing first-pass and systemic drug metabolism ✓
• C Inhibiting intestinal peptide transporters (PEPT1), reducing absorption of co-administered drugs
• D Increasing renal proximal tubular secretion of drug metabolites via OAT transporters

Explanation

Rifampicin is the most potent known enzyme inducer clinically. It binds and activates PXR (pregnane X receptor, a nuclear receptor), which upregulates transcription of CYP3A4, CYP2C8/9, CYP2C19, UGT enzymes, and the efflux transporter P-glycoprotein in the intestine and liver. The result is enhanced first-pass and systemic metabolism of co-administered substrates (e.g., oral contraceptives, warfarin, antiretrovirals, imatinib), dramatically reducing their plasma concentrations and efficacy. This is not mediated by protein binding competition, PEPT1 inhibition, or OAT-mediated renal secretion.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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