CYP2D6 interactions

CYP2D6 carries much of psychiatry and cardiology, cannot be induced by any available drug, and varies enormously between people by genotype.

About 7 per cent of people of European ancestry are poor metabolizers, and ultrarapid metabolizers are common in North and East Africa and the Arabian peninsula. Because no clinical inducer exists, the ultrarapid phenotype is the only thing that behaves like induction — levels run low and the drug appears to fail.

Inhibition is the commoner event and it is fast, appearing within hours and reversing over about five half-lives of the inhibitor. Bupropion, fluoxetine, paroxetine, quinidine and terbinafine are the strong inhibitors; abiraterone, cinacalcet, cobicistat, ritonavir, duloxetine, sertraline, mirabegron, rolapitant, amiodarone and MDMA fill in the rest. Fluoxetine and paroxetine are worth separating out because a patient can carry their inhibition for weeks after stopping.

The prodrugs invert everything. Codeine, tramadol and hydrocodone need 2D6 to form their active opioid, and tamoxifen needs it to form its active metabolite — so an inhibitor makes these drugs weaker, not stronger, while an ultrarapid metabolizer converts codeine fast enough to produce genuine opioid toxicity.

Ordinary substrates do the opposite and accumulate. The ones where that shows first are the antipsychotics haloperidol, risperidone, aripiprazole, brexpiprazole, iloperidone, perphenazine, thioridazine, chlorpromazine, fluphenazine and pimozide; the tricyclics amitriptyline, nortriptyline and desipramine; the beta-blockers metoprolol, carvedilol, nebivolol, timolol and the antiarrhythmics flecainide and propafenone; and atomoxetine, vortioxetine, tetrabenazine, deutetrabenazine, valbenazine, tolterodine, donepezil, metoclopramide and dextromethorphan.

The practical rule: before adding fluoxetine, paroxetine or bupropion, look down the list for a 2D6 prodrug that will stop working and a 2D6 substrate with a narrow margin that will start accumulating.