Enzyme:CYP2B6

CYP2B6 (cytochrome P450 2B6) is a hepatic drug-metabolizing enzyme of the cytochrome P450 superfamily, encoded by the CYP2B6 gene on chromosome 19q13.2. For most of the history of cytochrome P450 pharmacology it was treated as a minor and clinically unimportant enzyme: present at low and variable abundance in the liver, with no substrate of obvious consequence. That assessment turned out to be wrong, and the correction is one of the more striking reversals in the recent history of pharmacogenomics. CYP2B6 is now recognised as the principal metabolic route for several medicines of real clinical weight, above all the antiretroviral efavirenz, and its gene is one of the most extensively polymorphic in the entire cytochrome P450 family.

The turning point came in 2001, when Thomas Lang, Kathrin Klein, Ulrich Zanger, and colleagues at the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart published a systematic survey of the CYP2B6 gene and found extensive genetic polymorphism with a direct, measurable impact on enzyme expression and function in human liver. That paper, together with the recognition over the following few years that the variant allele it described governed the pharmacokinetics and the side-effect profile of efavirenz, rehabilitated CYP2B6 from a footnote into a clinically actionable enzyme with its own dosing guideline.

Tissue distribution

CYP2B6 is predominantly a hepatic enzyme. Its hepatic abundance is low compared with CYP3A4 (estimates put it in the range of 2 to 10% of total hepatic cytochrome P450 protein) but it is unusually variable between individuals, with reported ranges spanning more than an order of magnitude. Part of that variability is genetic, part is induction-driven, and part remains unexplained. Extrahepatic expression, including in the brain, has been described and is of interest for the centrally acting substrates, but the liver carries the clinically dominant share of CYP2B6-mediated metabolism.

Function and substrate spectrum

CYP2B6 catalyzes hydroxylation, N-dealkylation, and oxidation across a substrate set that, while not large, is clinically heavyweight: it includes a first-line antiretroviral, a widely used opioid-maintenance medicine, a major oxazaphosphorine chemotherapy agent, and a dissociative anesthetic. The standard in-vitro and in-vivo probe substrate is bupropion, whose hydroxylation to hydroxybupropion is a CYP2B6-specific reaction used to phenotype the enzyme.

The table below collects the clinically important CYP2B6 substrates with each entry tagged by the contribution CYP2B6 makes to overall clearance (or to bioactivation, where the medicine is a CYP2B6-activated prodrug): major (CYP2B6 is the predominant route), moderate (CYP2B6 contributes meaningfully but other routes carry comparable load), minor (CYP2B6 contributes but other pathways dominate), and partial (one of several substantial routes). The list is curated for clinical relevance and is not exhaustive; see Comprehensive substrate and interaction tables below for the authoritative maintained resources.

near-complete CYP2B6 substrate table (click to expand)

Substrate	Therapeutic class	CYP2B6 contribution	Clinical notes
Artemether	Antimalarial	major	CYP2B6 is a principal route; relevant to the large-scale use of artemisinin-combination therapy in malaria-endemic regions.
Bupropion	Antidepressant; smoking-cessation aid	major	The standard CYP2B6 probe substrate (hydroxylation to hydroxybupropion, an active metabolite).
Cyclophosphamide	Antineoplastic / immunosuppressant (oxazaphosphorine)	major	Bioactivation reaction. CYP2B6 is the dominant route converting cyclophosphamide to 4-hydroxycyclophosphamide, the active alkylating species. CYP2B6 genotype influences the activation rate.
Diazepam	Benzodiazepine	minor	N-demethylation is mostly CYP2C19 and CYP3A4; CYP2B6 contributes a small share.
Efavirenz	Antiretroviral (NNRTI)	major	The canonical CYP2B6 clinical-pharmacogenomic substrate. CYP2B6 poor metabolizers have high plasma efavirenz and elevated rates of CNS side effects; CPIC publishes genotype-guided dosing. See Clinical implications.
Ifosfamide	Antineoplastic (oxazaphosphorine)	major	Bioactivation reaction, analogous to cyclophosphamide.
Ketamine	Dissociative anesthetic; antidepressant	major	N-demethylation to norketamine is substantially CYP2B6-mediated (with a CYP3A4 contribution).
Meperidine	Opioid analgesic (pethidine)	partial	Mixed CYP2B6 + CYP3A4 + CYP2C19.
Methadone	Opioid (chronic pain; opioid use disorder)	major	CYP2B6 is now recognised as a principal route of methadone clearance, in particular for the S-enantiomer. CYP2B6 poor metabolizers have higher methadone exposure, relevant to the QT-prolongation and respiratory-depression risk of methadone.
Nevirapine	Antiretroviral (NNRTI)	partial	Mixed CYP2B6 + CYP3A4.
Propofol	Intravenous general anesthetic	partial	Predominantly cleared by glucuronidation; CYP2B6 contributes to the hydroxylation route.
Selegiline	MAO-B inhibitor (Parkinson disease)	major	CYP2B6 contributes substantially to selegiline metabolism.
Sertraline	SSRI antidepressant	partial	Mixed CYP2B6 + CYP2C19 + CYP2D6 + CYP3A4.
Sorafenib	Tyrosine kinase inhibitor (oncology)	partial	Mixed CYP3A4 + CYP2B6 + glucuronidation.
Tamoxifen	Anti-estrogen (breast cancer)	minor	CYP2D6 dominates the activation to endoxifen; CYP2B6 contributes a minor route.
Temazepam	Benzodiazepine	minor	Predominantly glucuronidated; CYP2B6 contribution is small.

Phenotype categories

CYP2B6 has a CPIC-recognised metabolizer-phenotype classification, used in the efavirenz dosing guideline. The categories span the full range from reduced to enhanced function:

• Ultrarapid metabolizer (UM): two increased-function alleles.
• Rapid metabolizer (RM): one normal-function and one increased-function allele.
• Normal metabolizer (NM): two normal-function alleles.
• Intermediate metabolizer (IM): one normal-function and one decreased- or no-function allele.
• Poor metabolizer (PM): two decreased- or no-function alleles.

For efavirenz, the clinically important tail of this distribution is the poor-metabolizer end: PMs accumulate efavirenz and are at elevated risk of central-nervous-system toxicity. The ultrarapid and rapid end matters in the opposite direction, raising the theoretical concern of subtherapeutic exposure, though in practice the poor-metabolizer problem has dominated the clinical and guideline literature.

Major variants

The CYP2B6 gene is among the most polymorphic in the cytochrome P450 family. The clinically dominant alleles:

• \*1, the reference normal-function allele.
• \*6, the single most important CYP2B6 variant, a haplotype defined by two SNPs in cis: rs3745274 (Gln172His, the 516G>T change) and rs2279343 (Lys262Arg, the 785A>G change). It is a decreased-function allele and it is strikingly common, with allele frequencies that reach 30 to 50% in many African and African-ancestry populations and remain substantial (15 to 30%) in European, East Asian, and other populations. \*6 is the principal driver of the high-efavirenz-exposure poor-metabolizer phenotype.
• \*18 (rs28399499, Ile328Thr), a no-function allele largely confined to African-ancestry populations, where it adds further to the loss-of-function allele burden.
• \*4 (rs2279343 alone, Lys262Arg), an increased-function allele, the basis of the rapid- and ultrarapid-metabolizer phenotypes.
• \*9 (rs3745274 alone, Gln172His), a decreased-function allele.

The high frequency of the decreased- and no-function alleles in African-ancestry populations is not a statistical curiosity. Efavirenz was, for many years, a WHO-recommended first-line component of antiretroviral therapy across sub-Saharan Africa, which means the populations carrying the largest burden of CYP2B6 loss-of-function alleles were also the populations most heavily exposed to the medicine whose toxicity those alleles amplify. This intersection of allele frequency and prescribing pattern is part of the clinical and ethical backdrop to the efavirenz pharmacogenomic story.

Inhibitors

CYP2B6 inhibition of clinical relevance is produced by:

• Ticlopidine and Clopidogrel, the thienopyridine antiplatelet agents, both of which inhibit CYP2B6. The clopidogrel interaction is notable because clopidogrel is itself bioactivated by CYP2C19, so the medicine sits in two different pharmacogenomic stories at once.
• Voriconazole and clotrimazole, azole antifungals with CYP2B6-inhibitory activity.

Inducers

CYP2B6 is readily inducible through the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) pathways, the same xenobiotic-sensing machinery that drives CYP3A4 induction. Clinically meaningful inducers include rifampin, carbamazepine, phenobarbital, and ritonavir. Efavirenz induces CYP2B6, which contributes to the autoinduction of its own metabolism over the first weeks of therapy, complicating the interpretation of early plasma concentrations.

Clinical implications, summary

Efavirenz dosing. This is the headline CYP2B6 clinical story. Efavirenz has a narrow band between the plasma concentrations needed for virologic suppression and the concentrations that produce central-nervous-system side effects: vivid dreams, dizziness, insomnia, impaired concentration, and in some patients depressed mood. CYP2B6 poor metabolizers accumulate efavirenz and are disproportionately affected. The pharmacogenetic association was established in the mid-2000s, notably by the Adult AIDS Clinical Trials Group study reported by Haas and colleagues, which linked the CYP2B6 516G>T genotype to both efavirenz exposure and CNS side effects. CPIC's 2019 guideline gives genotype-guided efavirenz dosing: poor metabolizers, and to a lesser degree intermediate metabolizers, can be given a reduced efavirenz dose that maintains virologic efficacy while lowering the CNS-toxicity burden.

Methadone. CYP2B6 is a principal route of methadone clearance, and CYP2B6 poor metabolizers have higher methadone plasma concentrations. This is clinically relevant because methadone carries dose-related risks of QT-interval prolongation and respiratory depression, and inter-individual variability in methadone pharmacokinetics is large and historically poorly explained. CYP2B6 genotype accounts for part of that variability, though methadone dosing remains a clinical rather than a genotype-guided exercise.

Cyclophosphamide and ifosfamide. CYP2B6 is the dominant enzyme bioactivating these oxazaphosphorine chemotherapy agents to their cytotoxic forms. CYP2B6 genotype has been studied as a determinant of cyclophosphamide efficacy and toxicity, but the evidence has not produced a dosing guideline, and cyclophosphamide is not dosed by CYP2B6 genotype in routine oncology practice.

Comprehensive substrate and interaction tables

The substrate and interaction tables on this page are curated for clinical relevance, not for completeness. Three authoritative external resources maintain comprehensive lists of CYP2B6 substrates, inhibitors, and inducers, and the wiki recommends them to any reader who needs an exhaustive look-up:

• Flockhart Cytochrome P450 Drug Interaction Table, maintained by the Department of Medicine at Indiana University School of Medicine. The most widely cited clinical-reference cytochrome P450 table; substrate-, inhibitor-, and inducer-tiered, updated regularly. Available at https://drug-interactions.medicine.iu.edu/.
• U.S. Food and Drug Administration Drug Development and Drug Interactions Table, the regulatory-grade list FDA uses for labeling and clinical-trial design decisions. Smaller than Flockhart but every entry is FDA-vetted. Available via the FDA Center for Drug Evaluation and Research clinical drug interaction page.
• PharmGKB, the pharmacogenomics knowledge base hosted at Stanford University; the CYP2B6 gene page indexes substrate-, inhibitor-, and inducer-relationships with their underlying primary literature, and links each gene-drug pair to the CPIC dosing guideline where one exists. Available at https://www.pharmgkb.org/.

For a comprehensive review of CYP2B6 covering polymorphism, mechanism, and clinical relevance in detail, the Zanger and Klein 2013 review in Frontiers in Genetics is the standard dedicated reference.

See also

• Enzyme:CYP3A4, Enzyme:CYP2D6, Enzyme:CYP2C19, Enzyme:CYP2C9, Enzyme:CYP1A2, Enzyme:UGT1A1 (other drug-metabolizing enzymes covered in the wiki)
• Efavirenz, Methadone, Bupropion, Cyclophosphamide (canonical clinical CYP2B6 examples)
• Category:Drug-metabolizing enzymes