CYP3A4 is the most abundant hepatic CYP450 isoenzyme. Rifampicin markedly induces CYP3A4 via the pregnane X receptor (PXR). The consequence for a patient taking rifampicin together with oral contraceptives (ethinylestradiol) is:
- A Reduced ethinylestradiol plasma levels due to enhanced CYP3A4-mediated hydroxylation and increased first-pass and systemic clearance ✓
- B Increased ethinylestradiol bioavailability due to rifampicin-mediated inhibition of first-pass CYP3A4 metabolism
- C Rifampicin competitively inhibits estrogen receptor binding, reducing OCP efficacy at the receptor level
- D Induction of UGT1A1 is the primary mechanism; glucuronidation of ethinylestradiol is markedly increased
Correct answer: A. Reduced ethinylestradiol plasma levels due to enhanced CYP3A4-mediated hydroxylation and increased first-pass and systemic clearance
Explanation
Rifampicin is a potent inducer of CYP3A4 (via PXR-mediated transcriptional upregulation). Ethinylestradiol is primarily metabolized by CYP3A4 (2-hydroxylation and other pathways). CYP3A4 induction markedly increases first-pass metabolism and systemic clearance of ethinylestradiol, reducing its plasma concentrations by 40–60%. This can cause contraceptive failure, and women on rifampicin should use additional/alternative contraception. Rifampicin acts through enzyme induction, not receptor antagonism.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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