View source for 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 [[Phenotype:CYP2B6 intermediate metabolizer|intermediate metabolizer]], the [[Phenotype:CYP2B6 normal metabolizer|normal metabolizer]], the [[Phenotype:CYP2B6 rapid metabolizer|rapid metabolizer]], and the [[Phenotype:CYP2B6 ultrarapid metabolizer|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|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|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.<ref name="desta2019">Desta Z, Gammal RS, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy. ''Clinical Pharmacology and Therapeutics''. 2019 Oct;106(4):726-733. PMID: 31006110.</ref>

'''Methadone (clearance).''' CYP2B6 is a principal route of [[Methadone|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|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]]

== References ==

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[[Category:Pharmacogenomic phenotypes]]