Acid-catalyzed Reaction of Ethanol and Oxazepam and Its Pharmacological Consequence

TIAN JIAN YANG AND SHEN K. YANG

Department of Pharmacology, F. Edward Hebert School of Medicine, Uniformed Services, University of the Health Sciences, Bethesda, Maryland 20814-4799 U.S.A.

ABSTRACT

   Oxazepam (OX), an anxiolytic drug in clinical use, reacts with ethanol in aqueous and anhydrous ethanol solutions and simulated gastric fluid to form 3-O-ethyloxazepam (EtOX). In simulated gastric fluid containing 30% (by volume) ethanol, approximately 9.5% of OX is converted to EtOX in 2 hr at 37 ???. Studies of this report indicate that the 3-hydroxyl group of OX is substituted by ethanol to form EtOX in acidic media. Pharmacokinetic studies in rats indicate that orally administered OX and EtOX at doses of 35 and 17.5 nmole/kg are absorbed to similar extents. EtOX is eliminated at a slower rate than OX. EtOX is less active than OX in two pharmacological activity tests in mice. It is known that ethanol and OX have additive effects in the central nervous system. The results of this study suggest that ingestion of ethanol shortly before, shortly after, or simultaneously with the intake of OX may result in the formation of EtOX in the strongly acidic medium of the stomach, reducing the pharmacological effects of OX.

Key words: Oxazepam, ethanol, 3-O-ethyloxazepam, simulated gastric fluid, acid-catalyzed ethanolysis