CYP2B6 interactions

CYP2B6 is a minor enzyme with a short substrate list, and it matters in psychiatry for exactly three drugs: bupropion, methadone and ketamine.

Bupropion is both a 2B6 substrate and, separately, a strong CYP2D6 inhibitor — the substrate half is what changes bupropion’s own level, the inhibitor half is what changes everyone else’s. Ketamine and esketamine are cleared here too, as are propofol, selegiline, cyclophosphamide and ifosfamide.

Methadone is where 2B6 becomes a safety question. The enzyme preferentially clears the S-enantiomer, which is the less analgesic one and the one responsible for QT prolongation, so anything that slows 2B6 raises the enantiomer you least want accumulating.

Efavirenz and nevirapine sit on both sides of the page: each is a 2B6 substrate and each induces the enzyme, so they lower their own exposure and that of co-prescribed methadone — a well-described cause of opioid withdrawal when antiretroviral therapy starts. Carbamazepine, phenytoin, phenobarbital, rifampin and St John’s wort induce in the usual way.

The inhibitors are clopidogrel, ticlopidine, orphenadrine and voriconazole. None is common enough to memorize as a pair; it is enough to check 2B6 when a methadone or bupropion level moves without an obvious cause.