Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
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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 (AUC0–6) in Caucasians (1057 μg/L/min) was 27% greater than South Asians (768 μg/L/min). Similarly, the post-induction midazolam AUC0–6 in Caucasians (308 μg/L/min) was 50% greater than South Asians (154 μg/L/min), while the post-inhibition midazolam AUC0–6 in Caucasians (1834 μg/L/min) was 41% greater than South Asians (1079 μg/L/min). The difference in baseline AUC0–6 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 AUC0–6 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.
KeywordsCaucasian Cytochrome P450 3A4 Inter-racial variability Inducibility Pharmacokinetics South Asian
Participated in research design: JCM, MJS, and AR.
Recruitment and screening of trial participants: MVD.
Performed sample analysis: MVD and LSW.
Performed data analysis: AR.
Wrote or contributed to the writing of the manuscript: MVD, JCM, MJS, and AR.
This study was supported by a project grant (1100179) from the National Health and Medical Research Council of Australia.
Compliance with ethical standards
Disclosure of conflicts of interests
All authors declare that there are no conflicts of interest. Linda S. Wood and Jean-Claude Marshall are employees and stock holders for Pfizer, World Wide Research and Development.
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