Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.
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AbstractWhat is known and objectiveThe oral plasma clearance of midazolam and the ratio of 6-hydroxycortisol (6-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6-OHF/F in healthy Chinese.MethodsSingle oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6-OHF concentrations were measured using UPLC.Results and discussionThere were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC(0-) values (2100 335 vs. 3139 +/- 2046 h.ng/mL, P = 0044) and higher CL/F values (116 +/- 016 vs. 088 +/- 048 L/h/kg, P = 0005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus.What is new and conclusionThere were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.
Acceptance Date11/08/2016
All Author(s) ListChan SW, Xiao Y, Hu M, Yin OQP, Chu TTW, Fok BSP, Lee VHL, Tomlinson B
Journal nameJournal of Clinical Pharmacy and Therapeutics
Year2016
Month10
Volume Number41
Issue Number5
PublisherWILEY-BLACKWELL
Pages552 - 558
ISSN0269-4727
eISSN1365-2710
LanguagesEnglish-United Kingdom
Keywords6-hydroxycortisol,cortisol,CYP3A,midazolam,polymorphism
Web of Science Subject CategoriesPharmacology & Pharmacy;Pharmacology & Pharmacy

Last updated on 2020-05-07 at 00:53