CYP3A5*1/*3 genotype influences the blood concentration of tacrolimus in response to metabolic inhibition by ketoconazole.

Objectives Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P-450 enzyme system and allows reduction in treatment costs. Enzyme activity is determined by a single nucleotide polymorphism ( * 1/* 3 ) in the CYP3A5 gene. Methods We prospectively investigated the impact of this polymorphism on tacrolimus concentration in a cohort of 79 renal transplant recipients on ketoconazole. Genotyping was carried out by using polymerase chain reaction-restriction fragment length polymorphism technique. Dose-adjusted trough level (C o ) was calculated at baseline and at 3, 7, 15, 30, and 60 days. Results The baseline C o was significantly lower in those with at least one * 1 allele [44.95 ± 14.12 vs. 63.43 ± 14.72 (ng/ml)/(mg/kg/day), P< 0.0001]. After starting ketoconazole in all genotypes, dose-normalized C o increased and the cost of therapy decreased. Compared with baseline, the magnitude of increase was 112% and 79% in those without and with * 1 allele, respectively (P<0.001). The cost savings were 32% and 39% in mycophenolate mofetil-treated and 47% and 61% in azathioprine-treated patients who were with and without one * 1 allele, respectively. Conclusion We show that the CYP3A5 * 1/ * 3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking * 1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentration.