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Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
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Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
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Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
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Journal Article
Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries
2018
Overview
PurposeCytochrome 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.MethodsThis 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.ResultsThe 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.ConclusionsSignificantly 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.
Publisher
Springer Nature B.V
Subject
