Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers.

A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam. The effect of sertraline on the plasma protein binding of diazepam was also studied. Sertraline 50 mg/day titrated over a 10-day period to 200 mg/day or placebo was administered for 32 days. A single intravenous dose of diazepam 10 mg was given before the start, and after 21 days of sertraline or placebo treatment. The pharmacokinetic analyses were based on data from 20 individuals. The systemic clearance of diazepam decreased by 32% (-0.100 ml/min/kg) in the sertraline group compared with a 19% decrease (-0.054 ml/min/kg) in the placebo group (p = 0.0266). However, this small difference (13%) between the 2 groups was not considered meaningful. Other than a prolonged time to maximum plasma concentration for N-demethyldiazepam, no other pharmacokinetic parameters were significantly altered by sertraline. The plasma protein binding of diazepam was unchanged by concomitant administration of sertraline. These results suggest that sertraline at the maximum recommended dosage under steady-state conditions, and demethylsertraline, the principal metabolite of sertraline, are unlikely to exert significant inhibitory effects on the CYP2C19 and CYP3A3/4 hepatic isoenzymes responsible for the metabolism of diazepam. Therefore, it would be expected that sertraline would, similarly, have a minimal effect on the pharmacokinetic profile of other drugs metabolised by these hepatic isoenzymes.