Effect of the P450 oxidoreductase*28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers

摘要

Purpose: To assess the influence of the P450 oxidoreductase*28 SNP (POR*28) on tacrolimus pharmacokinetics in the Chinese population. Methods: Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5*3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and POR*28 was genotyped by PCR-direct sequencing. Tacrolimus whole blood concentrations were determined by ultra performance liquid chromatography-tandem mass spectrometry and the pharmacokinetics analyses was evaluated by nonparametric methods. Results: The frequencies of CYP3A5*3 and POR*28 allele were 73.3 % and 29.6 %, respectively. No significant differences existed in tacrolimus pharmacokinetics between the POR*28 CC homozygotes (n = 32) and the POR*28 T allele (n = 39) in all subjects. The mean tacrolimus AUC0-24, AUC 0- and Cmax for the POR*28 CC (n = 14) homozygotes in CYP3A5 expressers (CYP3A5*1/*1 or*1/*3 genotype) were 71.5 ?38.9 h ng/mL, 94.3 ?58.3 h ng/mL and 17.6 ?9.8 ng/mL, which were much higher than the POR*28 CT heterozygotes (n = 17) of 46.7 ?24.9 h ng/mL, 57.4 ?33.9 h ng/mL and 11.2 ?6.4 ng/mL (P 0.05, respectively). We did not observe any significant differences in tacrolimus pharmacokinetics between the POR*28 CC homozygotes (n = 18) and POR*28 T carriers (n = 22) in CYP3A5 nonexpressers (CYP3A5*3/*3 carriers). Conclusions: The POR*28 CT genotype presented a significantly lower level of tacrolimus exposure (AUC, Cmax) compared with the POR*28 CC genotype in CYP3A5-expressing subjects. It suggested that the POR*28 genetic polymorphism might also be responsible for the marked interindividual variability of tacrolimus besides the CYP3A5*3 genetic polymorphism.