Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate

Sixty-one healthy men and women, aged 20 to 75 years, received single 0.25-mg doses of triazolam, a cytochrome P450 (CYP) 3A substrate benzodiazepine, and placebo in a double-blind crossover study. Among women, age had no significant effect on area under the triazolam plasma concentration curve (AUC) (Spearman r=0.14, P=.44) or clearance (r =-0.09, P=.62). Among men, AUC increased (r=0.43, P <.02) and clearance declined (r=-0.42, P <.02) with increasing age. Gender differences in triazolam kinetics were not apparent. Compared with placebo, triazolam impaired digit-symbol substitution test performance, increased observer-rated sedation, impaired delayed recall of information learned at 1.5 hours after dosing, and increased electroencephalographic beta amplitude. Among men, mean values of relative digit-symbol substitution test decrement (P <.002) and observer-rated sedation (P <.05) were significantly greater in elderly subjects compared with young subjects. Age-dependent differences among women reached significance for observer-rated sedation (P <.02). A combination of higher plasma levels and increased intrinsic sensitivity explained the greater pharmacodynamic effects of triazolam in elderly subjects. Although the findings are consistent with reduced clearance of triazolam in elderly men, individual variability was large and was not explained by identifiable demographic or environmental factors.