The Experts for Comprehensive, Convenient Personalized Health!
The Experts for Comprehensive, Convenient Personalized Health!
Summary: Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations.
CYP3A5
The CYP3A enzyme family, including CYP3A4, CYP3A5, and CYP3A7, account for the largest number of P450 enzyme expressed in the human liver and intestine and is responsible for over 50% of all drugs (Guengerich PF. 1999). In adults, the most relevant of these are the CYP3A4 and CYP3A5 enzymes. While CYP3A4 PMs phenotypes are rarely observed, nonfunctional CYP3A5 variant alleles are relatively common in most populations (Birdwell, et al. 2015). CYP3A5 alleles are classified according to functionality: normal function (*1), no function (*3, *6, and *7), and unknown function (*8 and *9) (Birdwell, et al. 2015; supp allele functionality). CYP3A5*3, *6, and *7 are shown to result in truncated mRNA transcripts and nonfunctional protein products (Kuehl, et al. 2001).
CYP3A5 and Tacrolimus
Tacrolimus is a drug commonly used for the prophylaxis of organ rejection in patients receiving organ transplants (eg., liver, kidney, heart), which acts by inhibiting calcineurin and subsequent production of cytokines involved in immune-mediated responses (Prograf_PI, 2021). Tacrolimus undergoes metabolism via CYP3A4, CYP3A5, and P-glycoprotein (Birdwell, et al. 2015). Serum concentrations of tacrolimus are shown to be strongly influenced by CYP3A5 polymorphism, with EMs and IMs demonstrating significantly lower trough concentrations of tacrolimus than PMs and requiring higher doses (1.5-2 times) to achieve similar blood concentrations. Therefore, therapeutic drug monitoring is generally recommended and in cases where the CYP3A5 genotype is known, individualized starting doses are advised.