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Infection CYP1A2 Inhibition — MRCPsych Paper B MCQ

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HardSchizophrenia & PsychosisInfection CYP1A2 InhibitionMRCPsych Paper B

A 42-year-old man taking a stable dose of clozapine develops acute bacterial pneumonia. His clozapine dose, caffeine intake and cigarette consumption are unchanged, and the only new medicine is amoxicillin. His C-reactive protein is 220 mg/L. He develops marked drowsiness, hypersalivation and myoclonus, and his trough clozapine concentration has risen from 0.42 mg/L to 1.10 mg/L. Which mechanism best explains this change?

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Correct answer: C — Cytokine-mediated downregulation of CYP1A2, reducing clozapine clearance

Explanation lettering: D = shown as B · B = shown as C · C = shown as D

The correct answer is B. Clozapine is metabolised principally by hepatic CYP1A2. Acute infection and systemic inflammation can release pro-inflammatory cytokines, including IL-6, which downregulate CYP activity. Reduced CYP1A2-mediated clearance may rapidly raise clozapine concentrations and cause dose-related toxicity such as sedation, hypersalivation, myoclonus and seizures. The high CRP and unchanged dose, smoking, caffeine intake and medication exposure support this mechanism. Acute inflammation does not induce CYP1A2 (A). Clozapine is extensively metabolised, so reduced filtration of unchanged drug is not the principal explanation (C). Amoxicillin is not a clinically important CYP1A2 inhibitor (D). Cigarette smoke induces CYP1A2 and tends to lower clozapine concentrations; unchanged smoking cannot explain the acute rise (E).

Reference: Leung JG et al. Infection and inflammation leading to clozapine toxicity and intensive care: a case series. Annals of Pharmacotherapy. 2014;48(6):801–805. https://pubmed.ncbi.nlm.nih.gov/24619948/