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

Abstract

To assess the influence of the P450 oxidoreductase *28 SNP (POR*28) on tacrolimus pharmacokinetics in the Chinese population. 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. 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, AUC0-∞ 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). 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.

DOI: 10.1007/s00228-012-1432-1

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@article{Zhang2012EffectOT, title={Effect of the P450 oxidoreductase *28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers}, author={Jingjing Zhang and Hua Zhang and Xiao-Liang Ding and Sheng Ma and Li-yan Miao}, journal={European Journal of Clinical Pharmacology}, year={2012}, volume={69}, pages={807-812} }