Background
Methoxycarbonyl etomidate (MOC-etomidate) is a rapidly metabolized and ultra-short 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 three 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 (GABAA) receptor modulatory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to directly activate α1(L264T)β2γ2L 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 cortisol production by adrenocortical cells.
Results
MOC-ECA's EC50 for loss-of-righting reflexes in tadpoles was 2.8 ± 0.64 mM as compared to a previously reported value of 8 ± 2 μM for MOC-etomidate. EC50s for direct activation of GABAA receptors were 3.5 ± 0.63 mM for MOC-ECA versus 10 ± 2.5 μM for MOC-etomidate. IC50 for inhibiting in vitro cortisol production by adrenocortical cells was 30 ± 7 μM for MOC-ECA versus 0.10 ± 0.02 μM for MOC-etomidate.
Conclusions
In all three biological assays, MOC-ECA's potency was approximately 300-fold lower than that of MOC-etomidate.