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CYP1A2 Induction Loss — MRCPsych Paper B MCQ

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ModerateSchizophrenia & PsychosisCYP1A2 Induction LossMRCPsych Paper B

A 35-year-old man with treatment-resistant schizophrenia has been stable on clozapine. He stops smoking cigarettes on admission to a smoke-free ward and starts nicotine replacement therapy. One week later, despite no change in clozapine dose and no evidence of infection, he develops increased sedation and his trough clozapine concentration is substantially higher. Which pharmacokinetic mechanism best explains this change?

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Correct answer: E — Loss of CYP1A2 induction by tobacco-smoke PAHs

Explanation lettering: C = shown as A · A = shown as B · E = shown as C · B = shown as E

The correct answer is B. Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A2, an important enzyme in clozapine metabolism. Smoking cessation removes this induction, reducing clozapine clearance and increasing its plasma concentration, sometimes sufficiently to cause sedation, seizures or other dose-related toxicity. Nicotine is not responsible for CYP1A2 induction, so nicotine replacement does not prevent the interaction and does not inhibit CYP1A2 (A). This is not primarily a change in first-pass extraction (C) or plasma-protein displacement (D). Clozapine is extensively metabolised before excretion, so reduced renal clearance of unchanged drug (E) does not explain the rise.

Reference: Medicines and Healthcare products Regulatory Agency. Smoking and smoking cessation: clinically significant interactions with commonly used medicines, pharmacokinetic interactions section, 2014. https://www.gov.uk/drug-safety-update/smoking-and-smoking-cessation-clinically-significant-interactions-with-commonly-used-medicines