Pharmacological Studies of Methoxycarbonyl Etomidate's Carboxylic Acid Metabolite

BACKGROUND: Methoxycarbonyl etomidate (MOC-etomidate) is a rapidly metabolized and ultrashort-acting etomidate analog that does not produce prolonged adrenocortical suppression after bolus administration. Its metabolite (MOC-ECA) is a carboxylic acid whose pharmacology is undefined. We hypothesized that MOC-ECA possesses significantly lower pharmacological activity than MOC-etomidate, accounting for the latter's very brief duration of hypnotic action and inability to produce prolonged adrenocortical suppression after bolus administration. To test this hypothesis, we compared the potencies of MOC-ECA and MOC-etomidate in 3 biological assays. METHODS: The hypnotic potency of MOC-ECA was assessed in tadpoles using a loss-of-righting reflexes assay. The gamma-aminobutyric acid type A (GABA(A)) receptor modulatory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to directly activate alpha(1)(L264T))beta(2)gamma(2L) GABAA receptors. The adrenocortical inhibitory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to inhibit in vitro codisol production by adrenocortical cells. RESULTS: MOC-ECA's 50% effective concentration for loss-of-righting reflexes in tadpoles was 2.8 +/- 0.64 mM as compared with a previously reported value of 8 +/- 2 mu M for MOC-etomidate. The 50% effective concentrations for direct activation of GABA(A) receptors were 3.5 +/- 0.63 mM for MOC-ECA versus 10 +/- 2.5 mu M for MOC-etomidate. The half-maximal inhibitory concentration for inhibiting in vitro cortisol production by adrenocortical cells was 30 +/- 7 mu M for MOC-ECA versus 0.10 +/- 0.02 mu M for MOC-etomidate. CONCLUSIONS: In all 3 biological assays, MOC-ECA's potency was approximately 300-fold lower than that of MOC-etomidate. (Anesth Analg 2012;115:305-8)