The influence of
propranolol coadministration or of cigarette smoking on the kinetics of
desmethyldiazepam following a single 20-mg intravenous dose of
clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous
clorazepate was given once in the control condition, and again during coadministration of
propranolol, 80 mg twice daily. Compliance with the prescribed
propranolol regimen was verified by measurement of serum
propranolol concentrations (mean, 37 ng/ml). In control vs
propranolol treatment conditions, there was no significant difference in
desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of
desmethyldiazepam half-life (55 vs 61 h, P less than 0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg, P less than 0.02) attributable to
propranolol. In Study Two,
desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and
body weight. There was no significant difference between controls and cigarette smokers in
desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus,
propranolol slightly although significantly impairs the clearance of
desmethyldiazepam and prolongs its half-life. Cigarette smoking has no apparent influence on
desmethyldiazepam kinetics.