Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
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Funding
This study was supported by a project grant (1100179) from the National Health and Medical Research Council of Australia.
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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.
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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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van Dyk, M., Marshall, JC., Sorich, M.J. et al. Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries. Eur J Clin Pharmacol 74, 913–920 (2018). https://doi.org/10.1007/s00228-018-2450-4
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DOI: https://doi.org/10.1007/s00228-018-2450-4