乙醇與oxazepam在胃酸中之化學反應及其對藥效之影響   全文下載

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

Oxazepam是用作治療焦慮之藥物。Oxazepam（OX）在酸性水溶液，無水乙醇，或模擬胃液中與乙醇起化學反應，產生3-O-ethyloxazepam（EtOX）。OX在37°C含有30%（體積比）乙醇之模擬胃液中，2小時後約有9.5%轉換成EtOX。本研究結果指出，OX在酸性溶液中其3位碳上之羥基被乙醇之乙氫基取代而形成EtOX。以大白鼠作藥物代謝動力學比較之結果顯示，口服OX與EtOX之吸收程度差別不大，而EtOX之排除速率比OX較慢。以小白鼠所作兩種藥效試驗之結果顯示，EtOX之藥效比OX較弱。文獻中報導同時服用酒精與OX對中樞神路系統會有加成性效應。本研究結果顯示在飲酒前後或同時進服OX一可能會在胃液的酸性條件下產生EtOX而導致OX本身之藥效降低。

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°C. 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.