CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients.

BACKGROUND

Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A422 and CYP3A53 variants on tacrolimus drug disposition in adult heart transplant recipients.

METHODS

The retrospective study included 76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A422 and CYP3A53, and combined genotypes were classified as follows: extensive metabolizers (EM, CYP3A41/1+CYP3A51 carriers), intermediate metabolizers (IM, CYP3A41/1+CYP3A53/3, or CYP3A422 carriers+CYP3A51 carriers), and poor metabolizers (PM, CYP3A422 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/mL per mg/d).

RESULTS

In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (P<.001) in CYP3A5 expressers vs non-expressers. When combined CYP3A genotypes were evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs vs IMs (P<.001) and EMs vs PMs (P=.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs vs PMs.

CONCLUSION

Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A53. These data suggest that CYP3A422 and combined CYP3A genotypes are unlikely to provide additional information beyond CYP3A5 genotype.