Clinical Information

CYP3A5 is a member of the CYP3A family of genes located on chromosome 7. The cytochrome P450 (CYP) 3A subfamily of enzymes responsible for the metabolism of more than 50% of medications that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells. The CYP3A5 expression level and enzymatic activity can be modulated by genetic variation. CYP3A5 allelic frequency depends upon ethnicity. For example, in individuals of European descent the most common allele is the CYP3A5*3 allele (c.219-237A>G), which results in a splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele (functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from 0.14 among sub-Saharan Africans to 0.95 in European populations.

CYP3A5 testing is commonly ordered for patients receiving tacrolimus. Tacrolimus is an immunosuppressive calcineurin inhibitor used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice.

Tacrolimus dose requirements are most closely associated with CYP3A5 genotype even though the drug is metabolized by both CYP3A4 and CYP3A5. According to existing literature and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, individuals with at least one copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) require a higher dose of tacrolimus to reach the targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie, *3/*3) (2-5). CYP3A5 genotyping may predict dose requirements for tacrolimus but does not replace the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended. One of the complications in interpreting CYP3A5 genotyping results and the effect of genotype on drug dosing is the fact that most individuals involved in drug trials have been of European decent. Individuals of European decent are more likely to have the CYP3A5*3/*3 genotype, which predicts a poor metabolizer phenotype. Dosing requirements were derived from these clinical trials so individuals with 1 or 2 copies of CYP3A5*1, will functionally behave as though they have increased activity and may require higher doses of CYP3A5 metabolized drugs.

The following table displays the CYP3A5 variants detected by this assay, the corresponding star allele, and the effect on CYP3A5 enzyme activity: