| OBJECTIVE1. To assess the effects of POR*28 polymorphism on CYP3A in vivo activity in healthy Chinese male volunteers by using midazolam (MID) as a probe drug.2. To investigate the effect of cytochrome P450 oxidoreductase (POR) polymorphisms on pharmacokinetics of anlodipine in male healthy volunteers.METHODS1. Effect of POR*28 genetic polymorphism on the CYP3A in vivo Activity in Healthy Chinese Male SubjectsPOR*28 polymorphism was genotyped in 73 healthy Chinese male subjects. Seven POR*28 CC homozygotes, eight POR*28 TT homozygotes, and seven CT heterozygotes were selected. A randomized, two-phase, open-label, crossover study was performed to assess in vivo CYP3A activity by both oral (reflective of intestinal and heptic CYP3A activity simultaneously) and intravenous (reflective of hepatic CYP3A activity) MID administration. Plasma concentration of MID and 1-hydroxy-midazolam (1-OH-MID) were determined by liquid chromatography-tandem mass spectrometry (LC-MS).2. Effect of POR*28 genetic polymorphism on the the pharmacokinetics of amlodipine 22 subjects were selected according to POR*28 polymorphism genotyped, which were the same as previous study.5 mg of amlodipine tablets was orally administrated. A series of blood samples were collected before and in 96 hours after administration. Plasma concentrations of amlodipine were measured by HPLC-MS-MS. The pharmacokinetic parameters were obtained by DAS Ver 2.0. The statistical analysis was performed with SPSS 13.0.RESULTS1. Effect of POR*28 genetic polymorphism on the CYP3A in vivo Activity in Healthy Chinese Male SubjectsThe allele frequency for the POR*28 T (503V) allele was 43.2%. The average age, weight, height and body mass index (BMI) of the 18 subjects recruited for CYP3A phenotyping were 23 (20-28) years,65.0 (57-75) kilogram (kg),1.74 (1.63-1.80) meter (m) and 22.01 (19.27-24.46) kg/m2, respectively. No difference in the demographic characteristics of the subjects was observed among the POR*28 genotype groups (p> 0.05). As compared with POR*28 CC homozygotes, POR*28 TT homozygotes showed significantly increased AUC0-8 of 1-OH-MID after intravenous ([86.15±24.34] vs [64.66±21.25] ng/mL/h,p=0.026) but not oral ([126.36±31.60] vs [93.92±29.28] ng/mL/h, p= 0.062) MID administration. POR*28 TT homozygotes also showed significantly higher 1-OH-MID Cmax ([51.40±10.72] ng/mL) than CC homozygotes ([31.47±11.54] ng/mL, p=0.001) and CT heterozygotes ([30.12±9.21] ng/mL, p=0.002) after intravenous MID administration. POR*28 TT homozygotes also showed significantly higher MID metabolic ratio (MR) than carriers of the POR*28 C allele (p=0.031) after intravenous MID injection. No difference in overall (hepatic plus intestinal) CYP3A in vivo activity as indicated by oral MID administration was observed among POR*28 genotypes.2. Effect of POR*28 genetic polymorphism on the the pharmacokinetics of amlodipineAUC0â†'t of amlodipine in individuals with the POR*28 CC, POR*28 CT,and POR*28 TT genotypes were (158.85±23.25), (135.73±33.22), and (155.90±43.18) ng/mL/h respectively. Cmax of amlodipine were (5.04±1.29),(3.96±1.12), and (6.28±2.42) ng/mL,respectively. Tmax of amlodipine were (5.86±3.63),(4.50±1.60), and (4.71±1.50) h,respectively. t1/2 of amlodipine were (38.12±15.82),(38.76±10.37), and (33.31±14.22) h, respectively. POR*28 TT homozygotes also showed significantly higher Cmax than carriers of the POR*28 CT allele. But there was no significant difference in other pharmacokinetics parameters among three genotype groups.CONCLUSION1. The POR*28 C>T polymorphism could increase 1-hydroxylation of MID after intravenous MID administration, and the polymorphism was associated with increased hepatic but not intestinal CYP3A activity in healthy Chinese volunteers.2. The POR*28 C>T polymorphism can increase metabolism of amlodipine, but has no significant difference on pharmacokinetics parameters among three genotypes. |
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