科研之友
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摘要
Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme.
This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin.
The geometric mean baseline midazolam area under the plasma concentration curve (AUC(0-6)) in Caucasians (1057 mu g/L/min) was 27% greater than South Asians (768 mu g/L/min). Similarly, the post-induction midazolam AUC(0-6) in Caucasians (308 mu g/L/min) was 50% greater than South Asians (154 mu g/L/min), while the post-inhibition midazolam AUC(0-6) in Caucasians (1834 mu g/L/min) was 41% greater than South Asians (1079 mu g/L/min). The difference in baseline AUC(0-6) between Caucasians and South Asians was statistically significant (p 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC(0-6) ratio, in both unadjusted and genotype adjusted analyses.
Significantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.
- 出版日期2018-7
