CYP2B6

CYP2B6 (cytochrome P450 2B6) is a metabolising enzyme found mainly in the liver, responsible for breaking down a select but significant group of psychoactive and pharmaceutical compounds. It belongs to the same cytochrome P450 superfamily as CYP3A4 and CYP2D6, but its substrate range is narrower — fewer drugs depend on it, yet for those that do, it can be the dominant clearance route.

Two properties set CYP2B6 apart from most metabolic enzymes. It is among the most genetically variable of all CYP enzymes — large portions of some populations carry alleles that substantially reduce activity, while others carry variants that accelerate it. And it is unusually prone to mechanism-based inactivation, in which a reactive intermediate formed during metabolism permanently disables the enzyme rather than merely competing with it.

How it works · its role

Like other CYP enzymes, CYP2B6 uses an iron-containing haem group to oxidise drug molecules, making them more water-soluble so the body can excrete them. Most of the time this proceeds without incident: the drug binds, is oxidised, and the enzyme is left intact.

Mechanism-based inactivation breaks that pattern. Certain substrates, once processed by CYP2B6, form reactive intermediates that bind covalently to the enzyme itself, permanently disabling it. Recovery depends on the liver synthesising fresh enzyme protein — a process that takes days. A second exposure to such a compound can therefore accumulate faster than the first, since part of the enzyme pool was knocked out by the earlier dose.

Genetic variation compounds this unpredictability. The CYP2B6*6 allele, present at meaningful frequencies across many populations, reduces catalytic activity markedly. Poor metabolisers — those carrying two low-activity alleles — can have plasma concentrations of CYP2B6 substrates considerably higher than extensive metabolisers on an identical dose.

Relevance to substances & effects

The clearest harm-reduction relevance of CYP2B6 is in opioid substitution therapy. Methadone is one of its principal substrates, and genetic variation in this enzyme is a recognised source of unexpected differences in plasma levels between patients on identical doses.

Inducers of CYP2B6 — including certain anticonvulsants and some antiretroviral drugs — can lower methadone levels enough to precipitate withdrawal; inhibitors can raise them, increasing sedation and cardiac risk. The interaction layer on substance pages is where specific pairings and their severity ratings are recorded.

Ketamine is also metabolised partly via CYP2B6, producing the active metabolite norketamine alongside CYP3A4. Bupropion, used for smoking cessation and depression, relies on this pathway as a primary metabolic route. MDMA interacts with CYP2B6 both as a substrate and as an inhibitor, contributing to its dose-dependent pharmacokinetics.

Because mechanism-based inactivation unfolds over repeated exposures rather than immediately, the effect of combinations involving CYP2B6 substrates and inhibitors is not always predictable from single-dose behaviour — a reason why interaction flags for CYP2B6-dependent compounds warrant particular attention.