TRIAZOLAM PHARMACOKINETICS AND PHARMACODYNAMICS IN CAUCASIANS AND SOUTHERN ASIANS - ETHNICITY AND CYP3A ACTIVITY

yA threefold higher area under the plasma drug concentration-time curv e (AUG) of nifedipine, a substrate of cytochrome P4503A (CYP3A), has b een shown in Southern Asians when compared with Caucasians. To determi ne if these differences are specific to nifedipine or apply to other s ubstrates of CYP3A, we examined the pharmacokinetics and pharmacodynam ics of 0.375 mg triazolam, another substrate of CYP3A, in eight health y Caucasians and eight healthy Southern Asians in a double-blind place bo-controlled study. When compared with Caucasians, Southern Asians ac hieved higher maximum plasma concentration (C-max) (8.0 +/- 2.6 us 4.8 +/- 1.9 ng ml(-1); the 95% confidence interval (CI) of the mean diffe rence was 0.76 to 5.7; P<0.01) and had a shorter time to reach maximal concentration (t(max)) (45 min (range 30-75) vs 90 min (range 60-145) ; the 95% CI of the mean difference was -69 to -20; P<0.002). Triazola m AUG, clearance and partial metabolic clearance did not differ signif icantly between Southern Asians and Caucasians. Significant difference s were found in postural sway after triazolam when compared with place bo in both Caucasians (double stance:eyes open (DSEO): 172.9 +/- 82.9 vs 1138.9 +/- 1182.4; the 95% CI of the mean difference was -1897.2 to -34.4; P < 0.04; and Southern Asians (DSEO: 216.2 +/- 80.9 vs 1086.0 +/- 827.1; the 95% CI of the mean difference was -1564.2 to -175.6; P= 0.02; double stance:eyes closed (DSEC): 207.5 +/- 89.8 vs 1156.9 +/- 9 32.1; the 95% CI of the mean difference was -1718.5 to -178.5; P=0.02; with no significant difference between the two ethnic groups. These r esults suggest that the large inter-ethnic difference in nifedipine cl earance are not generalizable to all CYP3A4 substrates.