title: Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology Research Lab, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Ding
authors.forename: Sheng
authors.initials: S
authors.lastname: Ma
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D000284:Administration, Oral; D000328:Adult; D054458:Amplified Fragment Length Polymorphism Analysis; D044466:Asian People / Q000235:genetics; D002681:China; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus