Enzyme:CYP3A4: Difference between revisions

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{| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"

|+ style="white-space:nowrap; text-align:left;" | near-complete CYP3A4 substrate table (click to expand)

! Substrate !! Therapeutic class !! CYP3A4 contribution !! Clinical notes

! scope="col" | Substrate !! scope="col" | Therapeutic class !! scope="col" | CYP3A4 contribution !! scope="col" | Clinical notes

|-

| [[Alfentanil]] || Opioid analgesic (anesthesia) || major || A classic CYP3A4 probe substrate; major substrate of CYP3A4 inhibitor interactions in the operating room.

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== Phenotype categories ==

~~Unlike~~ [[Enzyme:CYP2D6|CYP2D6]] ~~and several of~~ the CYP2C enzymes, ~~CYP3A4~~ does not ~~have~~ a ~~well~~-~~defined poor-metabolizer / intermediate / normal / ultrarapid~~ phenotype classification ~~useful at~~ the ~~bedside. Population~~ variability in CYP3A4 activity is wide (roughly 10- to 30-fold between individuals) ~~but~~ is dominated by environmental and physiological factors rather than by frankly inactivating star-allele genetics. The ~~clinically actionable polymorphisms~~ that ~~do exist are subtler~~ than the ~~corresponding stories at~~ CYP2D6 or CYP2C19.

CYP3A4 phenotyping is a more contested matter than the phenotyping of [[Enzyme:CYP2D6|CYP2D6]] or the CYP2C enzymes, and the two major pharmacogenomics consortia do not agree on it. The Clinical Pharmacogenetics Implementation Consortium (CPIC) does not assign CYP3A4 a metabolizer-phenotype classification; in CPIC's framing the population variability in CYP3A4 activity, though wide (roughly 10- to 30-fold between individuals), is dominated by environmental and physiological factors rather than by frankly inactivating star-allele genetics. The Dutch Pharmacogenetics Working Group (DPWG) takes the other position and does define a CYP3A4 phenotype, built around the decreased-function ''CYP3A4\*22'' allele: a poor metabolizer carries two ''\*22'' alleles, an intermediate metabolizer one, and a normal metabolizer none. The DPWG framework underlies that group's guidance on, for example, quetiapine dosing.<ref name="dpwg-cyp3a4">Dutch Pharmacogenetics Working Group (DPWG). Gene-drug interaction guideline for CYP3A4 (PharmGKB guideline annotation PA166265421). Royal Dutch Pharmacists Association (KNMP). Available via https://www.pharmgkb.org/.</ref> The wiki indexes the DPWG phenotype categories at [[Phenotype:CYP3A4 poor metabolizer]], [[Phenotype:CYP3A4 intermediate metabolizer]], and [[Phenotype:CYP3A4 normal metabolizer]]. Even under the DPWG framework, the CYP3A4 phenotype is a less settled construct than the CYP2D6 or CYP2C19 phenotypes, and environmental induction and inhibition remain the dominant sources of CYP3A4 variability whatever a patient's ''\*22'' genotype.

== Major variants ==

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* [[Enzyme:CYP3A5]], the related isoform with the more clinically actionable polymorphism

* [[Enzyme:CYP2D6]], [[Enzyme:CYP2C19]], [[Enzyme:CYP2C9]], [[Enzyme:CYP1A2]], [[Enzyme:CYP2B6]]

* [[Phenotype:CYP3A4 poor metabolizer]], [[Phenotype:CYP3A4 intermediate metabolizer]], [[Phenotype:CYP3A4 normal metabolizer]] (the DPWG CYP3A4 metabolizer phenotypes)

* [[Tacrolimus]], [[Simvastatin]], [[Midazolam]], [[Cyclosporine]] (canonical CYP3A4 substrate examples)

* [[Rifampin]], [[Clarithromycin]], grapefruit juice (canonical inducer and inhibitor examples)

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