Renal Cyp3a5-Expressing Genotype Decreases Tacrolimus-to-Dose Ratio in Small Cohort of Renal Transplant Recipients—Preliminary Report

Abstract

Previous reports have established that patient CYP3A5 allelic variability may be the most important genetic contributor to interindividual variation in tacrolimus exposure in renal transplant recipients. However, CYP3A5 protein is expressed in the allogenic kidney. The aim of this study was to investigate the role of the renal CYP3A5 genotype in tacrolimus concentration-to-dose ratio within 3 years posttransplant. A retrospective cohort study of 90 renal transplant recipients and their donors evaluated the effect of the CYP3A5 single-nucleotide polymorphism (rs776746) on tacrolimus exposure. The area under the curve for tacrolimus concentration-to-dose ratio within 3-year follow-up was calculated and compared in kidneys carrying at least 1 CYP3A5*1 allele and those carrying the CYP3A5*3/*3 genotype. A significant effect of CYP3A5 expression on tacrolimus exposure was observed in both donors (mean ± SD: 23.8 ± 7.9 vs 32.6 ± 7.4 ng/mL/mg, respectively; P < .001) and recipients (mean ± SD: 27.1 ± 8.0 vs 32.2 ± 7.9 ng/mL/mg, respectively; P=.034) and was lower when CYP3A5 enzyme occurred. Thus, new groups were formed: the group in which at least 1 of the pairs, donor or recipient, had a CYP3A5 expressing allele (n=23) had lower exposure to tacrolimus compared with nonexpressors (n=67; mean ± SD: 26.2 ± 7.6 vs 33.2 ± 7.4 ng/mL/mg, respectively; P < .001). Intrarenal metabolism of tacrolimus may affect both local and systemic drug exposure. Nonexpressors receiving kidneys with the CYP3A5*1 allele may benefit from higher tacrolimus doses to hasten achievement of target drug concentrations.