S W Chan1, Y Xiao1, M Hu1, O Q P Yin2, T T W Chu1, B S P Fok1, V H L Lee2, B Tomlinson1. 1. Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, NT, Hong Kong SAR, China. 2. School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, China.
Abstract
WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-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 6β-OHF/F in healthy Chinese. METHODS: Single 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 6β-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6β-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6β-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 AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6β-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6β-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.
WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-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 6β-OHF/F in healthy Chinese. METHODS: Single 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 6β-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6β-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6β-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 AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6β-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6β-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.
Authors: Brooks T McPhail; Chie Emoto; Tsuyoshi Fukuda; Dawn Butler; Jason R Wiles; Henry Akinbi; Alexander A Vinks Journal: J Clin Pharmacol Date: 2019-12-09 Impact factor: 3.126