The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam

Abstract

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD) were evaluated in twelve healthy non-smokers (NS) and twelve smokers (S, > or = 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained-release tablets in an open-label, parallel-group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8 +/- 25.8 versus 48.2 +/- 14.01 h-1) or peak adinazolam plasma concentrations (Cmax) (93.3 +/- 31.8 versus 90.4 +/- 18.0 ng ml-1) between groups. NDMAD AUC (2541 +/- 457 versus 2798 +/- 447 ng h ml-1) and Cmax (173 +/- 30.3 versus 175 +/- 26.9 ng ml-1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non-smokers (8.7 +/- 0.7 versus 10.7 +/- 2.71 h-1; p < 0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol-digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.