EFFECT OF VALPROATE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF LORAZEPAM

The pharmacokinetic-pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double-blind, placebo-cont rolled crossover study. Sixteen healthy male volunteers enrolled in th e study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12-day period. In both peri ods, lorazepam (1 mg every 12 hours) was administered on days 6 throug h 9 and on the morning of day 10. Concomitant administration of divalp roex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady-state maximum plasma concentration, area under the concentrati on-time curve, and trough plasma concentrations of lorazepam, respecti vely The apparent clearance of lorazepam through the formation of lora zepam glucuronide was reduced by 31% during coadministration of divalp roex sodium. Pharmacokinetic properties of valproate did not change si gnificantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant di fferences in sedation between the two regimens. It is concluded that v alproate increases plasma concentrations and reduces clearance of lora zepam, most likely by impairing hepatic glucuronidation, and that coad ministration of lorazepam does not affect the steady-state pharmacokin etic properties of valproate.