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Lorazepam‐Valproate Interaction: Studies in Normal Subjects and Isolated Perfused Rat Liver
Author(s) -
Anderson Gail D.,
Gidal Barry E.,
Kantor Eric D.,
Wilensky Alan J.
Publication year - 1994
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1994.tb02937.x
Subject(s) - lorazepam , glucuronide , pharmacology , drug interaction , drug , metabolism , chemistry , valproic acid , phenytoin , intravenous bolus , bolus (digestion) , anticonvulsant , pharmacokinetics , epilepsy , medicine , anesthesia , biochemistry , psychiatry
Summary: Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly 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.