title: Effects of the CYP oxidoreductase Ala503Val polymorphism on CYP3A activity in vivo: a randomized, open-label, crossover study in healthy Chinese men.
abstract: BACKGROUND
  Cytochrome P450 (CYP) oxidoreductase (POR) is the electron donor for microsomal CYP enzymes. The POR Ala503Val (POR*28 C > T) polymorphism has been reported to influence CYP3A activity in vivo in a white population. The influence of this polymorphism on CYP3A activity in vivo in the Chinese population currently unknown.
  
  
  OBJECTIVE
  This study was designed to assess the influence of the POR*28 polymorphism on the CYP3A activity in vivo in healthy Chinese men using midazolam (MID) as a probe drug.
  
  
  METHODS
  The POR*28 polymorphism was genotyped in healthy Chinese men. A randomized, 2-phase, open-label, crossover study was performed to assess in vivo CYP3A activity after both oral and intravenous MID administration, which reflect both intestinal and hepatic CYP3A or only hepatic CYP3A activity, respectively. The plasma concentrations of MID and 1-hydroxy-midazolam (1-OH-MID) were determined by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  A total of 73 healthy Chinese men were enrolled (CC genotype, 21 subjects; TT genotype, 11; CT genotype, 41), 22 of whom were selected for additional phenotyping of the CYP3A5*3 polymorphism (CC, 7; TT, 8; CT, 7). The mean (range) age, weight, height, and body mass index of the 22 subjects were 23 (20-28) years, 65.0 (57-75) kg, 1.74 (1.63-1.80) m, and 22.01 (19.27-24.46) kg/m(2), respectively. The frequency of the POR*28 T (503V) allele was 43.2%. No significant differences in the demographic characteristics of the subjects were observed between the POR*28 genotype groups. All of the POR*28 CC and TT homozygotes and 2 of the POR*28 CT heterozygotes carried the CYP3A5*3/*3 genotype (CYP3A5 low expressors); 6 CT heterozygotes carried the CYP3A5*1 allele (CYP3A5 expressors). The mean (SD) 1-OH-MID AUC(0-8) was significantly greater in the TT homozygotes compared with the CT heterozygotes after intravenous (86.15 [24.34] vs 53.21 [31.36] ng/mL/h; P = 0.026) but not oral (126.36 [31.60] vs 103.09 [31.00] ng/mL/h; P = 0.159) MID administration. Mean 1-OH-MID C(max) was significantly greater in the TT homozygotes (51.40 [10.72] ng/mL) compared with the CC homozygotes (31.47 [11.54] ng/mL; P = 0.002) and CT heterozygotes (30.12 [9.21] ng/mL; P = 0.001) after intravenous MID administration. After intravenous MID injection, the MID metabolic ratio was significantly greater in the TT homozygotes compared with carriers of the C allele (P = 0.031). Based on these findings, no significantly differences in overall (hepatic plus intestinal) CYP3A in vivo activity were observed between the POR*28 genotypes.
  
  
  CONCLUSIONS
  These findings suggest that individuals with the POR*28 C > T polymorphism underwent an increase in 1-hydroxylation of MID after intravenous MID administration, and that the polymorphism was associated with increased hepatic, but not intestinal, CYP3A activity in these healthy Chinese volunteers.
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Yang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Fu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: Heng
authors.initials: H
authors.lastname: Yang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Huang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Ouyang
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Tan
authors.forename: Hongyi
authors.initials: H
authors.lastname: Tan
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Huang
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D044466:Asian People / Q000235:genetics*; D001711:Biotransformation; D002681:China; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D007275:Injections, Intravenous; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012737:Sex Factors; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D008874:Midazolam