Phenotype:CYP2B6 poor metabolizer

A CYP2B6 poor metabolizer (PM) is a person who carries two decreased-function or no-function CYP2B6 alleles and therefore has substantially reduced CYP2B6 enzyme activity. It is one of the five metabolizer phenotypes assigned from CYP2B6 genotype, the others being the intermediate metabolizer, the normal metabolizer, the rapid metabolizer, and the ultrarapid metabolizer. This page describes the poor-metabolizer phenotype; the enzyme itself, including its history as a long-neglected and then rehabilitated enzyme, is covered at Enzyme:CYP2B6.

The clinically dominant CYP2B6 substrate is the antiretroviral efavirenz, and for efavirenz CYP2B6 is a clearance enzyme: the poor metabolizer clears efavirenz slowly, accumulates it, and is at elevated risk of its concentration-dependent central-nervous-system toxicity.

Genotype basis

The poor-metabolizer phenotype is produced by a CYP2B6 diplotype combining two decreased-function or no-function alleles. The clinically important alleles:

• \*6, the single most important CYP2B6 variant, a decreased-function haplotype. It is strikingly common, reaching allele frequencies of 30 to 50% in many African and African-ancestry populations and remaining substantial elsewhere.
• \*18, a no-function allele largely confined to African-ancestry populations.

Diplotypes such as \*6/\*6, \*6/\*18, and \*18/\*18 produce the poor-metabolizer phenotype. The full allele catalogue is maintained at PharmVar and described on the Enzyme:CYP2B6 page.

Population frequency

Because the \*6 allele is so common, the CYP2B6 poor-metabolizer phenotype is correspondingly common, and it is most common in African and African-ancestry populations, where \*6 allele frequencies are highest and the \*18 allele adds further loss-of-function burden. This distribution is not a statistical footnote: efavirenz was for many years a WHO-recommended first-line antiretroviral across sub-Saharan Africa, so 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.

Clinical consequences

Efavirenz (clearance; raised exposure). 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. A CYP2B6 poor metabolizer accumulates efavirenz and is disproportionately affected. CPIC's guideline gives genotype-guided efavirenz dosing, under which a poor metabolizer can be given a reduced efavirenz dose that maintains virologic efficacy while lowering the central-nervous-system burden.

Methadone (clearance). CYP2B6 is a principal route of methadone clearance, and a poor metabolizer reaches higher methadone plasma concentrations. This matters because methadone carries dose-related risks of QT-interval prolongation and respiratory depression, although methadone dosing remains a clinical rather than a genotype-guided exercise.

Cyclophosphamide (activation; reduced activation). For cyclophosphamide, CYP2B6 performs the opposite role: it is the dominant enzyme bioactivating the prodrug to its cytotoxic form. A poor metabolizer activates cyclophosphamide more slowly. The clinical significance of this has been studied but has not produced a dosing guideline.

See also

• Enzyme:CYP2B6, the enzyme, its history, and its full substrate spectrum.
• Phenotype:CYP2B6 intermediate metabolizer, Phenotype:CYP2B6 normal metabolizer, Phenotype:CYP2B6 rapid metabolizer, Phenotype:CYP2B6 ultrarapid metabolizer, the sibling phenotypes.
• Efavirenz, Methadone, Cyclophosphamide (representative affected medicines).
• Category:Pharmacogenomic phenotypes