Abstract
ET-26-HCl, a novel anaesthetic agent with promising pharmacological properties, lacks extensive studies on pharmacokinetics and disposition in vitro and in vivo. In this study, we investigated the metabolic stability, metabolite production and plasma protein binding (PPB) of ET-26-HCl along with its tissue distribution, excretion and pharmacokinetics in animals after intravenous administration. Ultra-high performance liquid chromatography–tandem quadrupole time-of-flight mass spectrometry identified a total of eight new metabolites after ET-26-HCl biotransformation in liver microsomes from different species. A hypothetical cytochrome P450-metabolic pathway including dehydrogenation, hydroxylation and demethylation was proposed. The PPB rate was highest in mouse and lowest in human. After intravenous administration, ET-26-HCl distributed rapidly to all tissues in rats and beagle dogs, with the highest concentrations in fat and liver. High concentrations of ET-26-acid, a major hydroxylation metabolite of ET-26-HCl, were found in liver, plasma and kidney. Almost complete clearance of ET-26-HCl from plasma occurred within 4 h after administration. Only a small fraction of the parent compound and its acid form were excreted via the urine and faeces. Taken together, the results added to a better understanding of the metabolic and pharmacokinetic properties of ET-26-HCl, which may contribute to the further development of this drug.
Highlights
Etomidate, R-1-(1-ethylphenyl) imidazole-5-ethyl ester, is an imidazole-based anaesthetic agent, commonly used as a short-acting intravenous agent for anaesthesia and sedation because of its favourable myocardial performance [1,2]
Monkey, dog, rat and mouse were purchased from Becton, Dickinson and Company (Franklin Lake, New Jersey, USA)
A significant amount of parent compound was found in the human microsome, whereas there was none or little residual amount of ET-26-HCl in liver microsomes from other species, which were mainly O-demethylated and dehydrogenated O-demethylated metabolites
Summary
R-1-(1-ethylphenyl) imidazole-5-ethyl ester, is an imidazole-based anaesthetic agent (figure 1a), commonly used as a short-acting intravenous agent for anaesthesia and sedation because of its favourable myocardial performance [1,2]. ET-26-HCl exhibited superior anaesthetic property, reduced adrenal suppression and optimal myocardial performance [6,7,8,9,10]. Given these outstanding features, determining the pharmacokinetic and in vivo disposition of ET-HCl-26 becomes imperative. ET-26-acid (etomidate acid, figure 1c) is reported as the main inactive ester hydrolysis-generated metabolite of ET-26-HCl [7]. It was reported that ET-26-HCl was rapidly cleared within 4 h of intravenous administration in rats, and the metabolite, ET-26-acid, had a higher plasma exposure than the parent drug [11]
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