Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries

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 (AUC _0–6 ) in Caucasians (1057 μg/L/min) was 27% greater than South Asians (768 μg/L/min). Similarly, the post-induction midazolam AUC _0–6 in Caucasians (308 μg/L/min) was 50% greater than South Asians (154 μg/L/min), while the post-inhibition midazolam AUC _0–6 in Caucasians (1834 μg/L/min) was 41% greater than South Asians (1079 μg/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. 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.