Metabolite-inactive etomidate analogues alleviating suppression on adrenal function in Beagle dogs

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• 作者：Jun Yang^a ; ¹ ; Yi Kang^a ; ¹ ; Bin Wang^a ; Linghui Yang^a ; Jin Liu^a ; ^b ; Wensheng Zhang^a ; ^b ; ^{zhang_ws@scu.edu.cn}
• 关键词：Etomidate analogues ; Reduced corticosteroid suppression ; Slow metabolism ; Inactive metabolite ; Intravenous anaesthetic drug
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 March 2017
• 年：2017
• 卷：99
• 期：Complete
• 页码：343-349
• 全文大小：557 K
• 卷排序：99

文摘

Owing to rapid generation in body, the metabolites of etomidate softdrug are able to accumulate in either the brain or periphery and subsequently affect the recovery from anaesthesia or cause corticosteroid suppression. This study was designed to investigate the ability of two etomidate analogues (ET-26, ET-42) with inactive metabolites to provide anaesthesia with lesser corticosteroid suppression. The 50% effective dose (ED50) of ET-26, ET-42, Etomidate, MOC-ET (an etomidate softdrug) and CPMM (an improved etomidate softdrug) required to induce anaesthesia intravenously in Beagle dogs were 1.44 mg/kg, 0.72 mg/kg, 0.43 mg/kg 23.12 mg/kg and 0.59 mg/kg, respectively. After adrenocorticotropic hormone (ACTH) stimulation, the serum concentrations of cortisol and corticosterone in the ET-26, ET-42 and CPMM groups were similar to those of controls, and significantly higher than those of the etomidate and MOC-etomidate groups (P < 0.05). Furthermore, no significant differences in serum concentrations of cortisol and corticosterone after ACTH-stimulation between ET-26, ET-42, CPMM, and blank control groups were observed. In this study, anaesthetic potencies of ET-26 (ED50 = 1.44 mg/kg) and ET-42 (ED50 = 0.72 mg/kg) were determined. Both analogues can significantly reduce the corticosteroid suppression in vivo. Metabolite-inactive etomidate derivatives with slow metabolism might provide a novel strategy to improve Etomidate associated corticosteroid suppression.