Rifampicin and St John's Wort both cause therapeutic failure of concurrently administered drugs (e.g., oral contraceptives, antiretrovirals) by which shared mechanism?
- A Competitive inhibition of CYP3A4 in the intestinal wall and liver
- B Transcriptional upregulation of CYP3A4 and P-glycoprotein via activation of the pregnane X receptor (PXR) ✓
- C Irreversible suicide inhibition of CYP2D6
- D Inhibition of UGT1A1-mediated glucuronidation in the enterocytes
Explanation
Rifampicin and hyperforin (active constituent of St John's Wort) are potent agonists of the pregnane X receptor (PXR, NR1I2), a nuclear receptor that heterodimerises with RXR and transcriptionally induces CYP3A4, CYP2C9, and the drug efflux transporter P-glycoprotein (MDR1) in hepatocytes and enterocytes. This massively increases first-pass metabolism and efflux of co-administered drugs, reducing their systemic bioavailability. This is enzyme induction, not inhibition; inhibitors (e.g., ketoconazole, grapefruit) cause the opposite effect. CYP2D6 suicide inhibition is the mechanism of drugs like paroxetine and haloperidol.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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