Triazolam pharmacokinetics and pharmacodynamics in Caucasians and Southern Asians: ethnicity and CYP3A activity.
A threefold higher area under the plasma drug concentration-time curve (AUC) of nifedipine, a substrate of cytochrome P4503A (CYP3A), has been shown in Southern Asians when compared with Caucasians. To determine if these differences are specific to nifedipine or apply to other substrates of CYP3A, we examined the pharmacokinetics and pharmacodynamics of 0.375 mg triazolam, another substrate of CYP3A, in eight healthy Caucasians and eight healthy Southern Asians in a double-blind placebo-controlled study. When compared with Caucasians, Southern Asians achieved higher maximum plasma concentration (Cmax) (8.0 +/- 2.6 vs 4.8 +/- 1.9 ng ml-1; the 95% confidence interval (CI) of the mean difference was 0.76 to 5.7; P < 0.01) and had a shorter time to reach maximal concentration (tmax) (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). Triazolam AUC, clearance and partial metabolic clearance did not differ significantly between Southern Asians and Caucasians. Significant differences were found in postural sway after triazolam when compared with placebo 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 +/- 932.1; 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 results suggest that the large inter-ethnic difference in nifedipine clearance are not generalizable to all CYP3A4 substrates.
Kinirons
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Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA.
Lang
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He
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Ghebreselasie
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Shay
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Robin
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Wood
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D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D007194:India / Q000208:ethnology; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D004856:Postural Balance / Q000187:drug effects; D014229:Triazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D014481:United States; D044465:White People
D006993:Hypnotics and Sedatives; D014229:Triazolam; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human