LORAZEPAM-VALPROATE INTERACTION - STUDIES IN NORMAL SUBJECTS AND ISOLATED-PERFUSED RAT-LIVER

Valproate (VPA) has been shown to interact with all the major antiepil eptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recentl y, evidence showed that VPA inhibits the elimination of drugs metaboli zed by glucuronide conjugation. Lorazepam (LZP), which is primarily el iminated by conjugation with glucuronic acid, is administered concurre ntly with VPA both in treatment of epilepsy and in patients treated wi th VPA for psychiatric disorders. Therefore, a significant drug intera ction is likely. We investigated such interaction both in in vitro iso lated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, int ravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significant ly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/ h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.