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

Abstract：

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, 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). 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.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Zhang JJ,Zhang H,Ding XL,Ma S,Miao LY

doi

10.1007/s00228-012-1432-1

subject

Has Abstract

pub_date

2013-04-01 00:00:00

pages

807-12

issue

eissn

0031-6970

issn

1432-1041

journal_volume

pub_type

临床试验,杂志文章

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