Clinical Information

CYP3A5 is 1 of the 4 CYP3 genes localized in tandem on chromosome 7 that encode the CYP3A subfamily of enzymes responsible for the metabolism of more than 50% of medications. CYP3A5 is expressed in liver, as well as extrahepatic tissue such as small intestine, lung, kidney, breast, and prostate. 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.

In general, most drugs metabolized by CYP3A5 are also metabolized by CYP3A4, with few exceptions. For this reason, substrates of these 2 enzymes are listed together in most publications and genotyping of both genes might be needed to fully understand the metabolism of these drugs and predict phenotype. The clinical relevance of CYP3A4 and CYP3A5 activity on drug metabolism has not been fully explored in many cases.

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 closely associated with CYP3A5 genotype. Broadly accepted dosing algorithms for use of genotype in dosing of tacrolimus have not been published, although the results of research conducted by Thervet et al(1) provide some guidance on initial dosing. According to existing literature, individuals with at least 1 copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) typically 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). CYP3A5*3 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.