The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam

Abstract

12 obese patients, pair-matched with 12 normal subjects, received a single 1 mg oral dose of alprazolam. Nine similar subject pairs received a single 0.5 mg oral dose of triazolam. Oral volume of distribution (Vd) was much greater in obese than control subjects for alprazolam (mean 114 vs 73L, p less than 0.001), but there was no difference between the 2 groups for triazolam (117 vs 116L). Apparent oral clearance (not corrected for body weight) of alprazolam was lower, although not significantly so, in obesity (66 vs 88 ml/min), but for triazolam it was much lower in the obese (340 vs 531 ml/min, p less than 0.005). Elimination half-life, which is dependent on both Vd and clearance, was prolonged in obesity for alprazolam (22 vs 11h, p less than 0.001) due to the increase in Vd, and also for triazolam (4.1 vs 2.6 h, p less than 0.025) because of the decreased clearance. Plasma protein binding was unchanged in obese compared with control subjects for both alprazolam and triazolam. During long term administration alprazolam should therefore take longer to reach steady-state concentrations in obese patients but the final levels achieved should be no different than for patients of normal bodyweight, provided dosage is adjusted for ideal rather than total bodyweight. In contrast, triazolam has impaired clearance in obesity. However, if given once-daily it still would not accumulate with long term dosing due to its short half-life relative to the interval between doses.