EFFECTS OF GENETICALLY-DETERMINED S-MEPHENYTOIN 4-HYDROXYLATION STATUS AND CIGARETTE-SMOKING ON THE SINGLE-DOSE PHARMACOKINETICS OF ORAL ALPRAZOLAM

This study examines the effects of genetically determined S-mephenytoi n 4-hydroxylation capacity and cigarette smoking on the single-dose ph armacokinetics of oral alprazolam in 12 healthy male volunteers. Six s ubjects each were extensive metabolizers (EMs) and poor metabolizers ( PMs) of S-mephenytoin 4-hydroxylation. Seven subjects were smokers (>1 0 cigarettes/day), and five were nonsmokers, according to their self-r eports. Each subject took a single oral close of 0.8 mg of alprazolam, and blood samples were collected up to 48 hours postdose. Psychomotor function was assessed at times of blood samplings using the Digit Sym bol Substitution Test (DSST), Visual Analog Scale (VAS), and UKU Side Effect Rating Scale. Plasma alprazolam concentrations were measured by a high-performance liquid chromatography assay. None of the mean phar macokinetic parameters was significantly different between the EM and PM phenotype groups. Although the mean elimination half-life was signi ficantly shorter in the smoker group (p < .01) than in the nonsmoker g roup (13.1 +/- 2.9 vs. 20.0 +/- 2.7 hours, mean +/- SD), other pharmac okinetic parameters did not differ significantly between the two group s. Psychomotor function parameters did not differ significantly either between the EM and PM groups or between the nonsmoker and smoker grou ps. The present study thus suggests that neither S-mephenytoin 4-hydro xylation status nor self-reports of extensive cigarette smoking has a major impact on the metabolism of alprazolam in humans.