Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate: The Role of the Metabolite

Abstract

Background: Methoxycarbonyl etomidate (MOC-etomidate) and cyclopropyl methoxycarbonyl metomidate (CPMM) are rapidly metabolized "soft" etomidate analogs. CPMM's duration of hypnotic effect is context insensitive, whereas MOC-etomidate's is not. In this study, we tested the hypothesis that CPMM's effect is context insensitive because, unlike MOC-etomidate, its metabolite fails to reach physiologically important concentrations in vivo even with prolonged continuous infusion.

Methods: We compared the potencies with which MOC-etomidate and CPMM activate α1(L264T)β3γ2 γ-aminobutyric acid type A receptors and induce loss-of-righting reflexes (i.e., produce hypnosis) in tadpoles with those of their metabolites (MOC-etomidate's carboxylic acid metabolite [MOC-ECA] and CPMM's carboxylic acid metabolite [CPMM-CA], respectively). We measured metabolite concentrations in the blood and cerebrospinal fluid of Sprague-Dawley rats on CPMM infusion and compared them with those achieved with MOC-etomidate infusion. We measured the rates with which brain tissue from Sprague-Dawley rats metabolize MOC-etomidate and CPMM.

Results: Both analogs and their metabolites enhanced γ-aminobutyric acid type A receptor function and induced loss-of-righting reflexes in a concentration-dependent manner. However, in these 2 assays, CPMM-CA's potency relative to its parent hypnotic was approximately 1:4900 and 1:1900, respectively, whereas MOC-ECA's was only approximately 1:415 and 1:390, respectively. With 2-hour CPMM infusions, CPMM-CA reached respective concentrations in the blood and cerebrospinal fluid that were 2 and >3 orders of magnitude lower than that which produced hypnosis. CPMM was metabolized by the brain tissue at a rate that is approximately 1/15th that of MOC-etomidate.

Conclusions: Hypnotic recovery after CPMM administration is context insensitive because its metabolite does not accumulate to hypnotic levels in the central nervous system. This reflects the very large potency ratio between CPMM and CPMM-CA and the resistance of CPMM to metabolism by esterases present in the brain.

Figure 1

Structures of parent hypnotics and their carboxylic acid metabolites. (A) Methoxycarbonyl etomidate (MOC-etomidate) and MOC-ECA. (B) Cyclopropyl methoxycarbonyl metomidate (CPMM) and CPMM-CA.

Figure 2

Two-step synthesis of CPMM-CA. ET3N is triethylamine. DCM is dichloromethane.

Figure 3

Concentration-response relationships for direct activation of α₁(L264T)β₃γ₂ gamma-aminobutyric acid (GABA) type A receptors by each metabolite and its parent hypnotic. (A) Methoxycarbonyl etomidate (MOC-etomidate) and MOC-ECA. MOC-ECA was 415-fold less potent than was MOC-etomidate. (B) Cyclopropyl methoxycarbonyl metomidate (CPMM) and CPMM-CA. CPMM-CA was approximately 4,900-fold less potent than was CPMM. Data for CPMM were taken from Reference . In both panels, each data point is the mean value (± SD) derived from 6 oocyte experiments.

Figure 4

Concentration-response relationships for loss-of-righting reflexes in tadpoles by each metabolite and its parent hypnotic. (A) Methoxycarbonyl etomidate (MOC-etomidate) and MOC-ECA. MOC-ECA was 390-fold less potent than was MOC-etomidate. (B) Cyclopropyl methoxycarbonyl metomidate (CPMM) and CPMM-CA. CPMM-CA was approximately 1,900-fold less potent than was CPMM. In both panels, each data point was obtained using 5 tadpoles. Data for MOC-etomidate and MOC-ECA were from Reference and that for CPMM were from Reference .

Figure 5

Blood metabolite concentrations with continuous infusions of parent hypnotic. MOC-etomidate was infused for 30 minutes and cyclopropyl methoxycarbonyl metomidate (CPMM) was infused for 120 minutes. All infusions were begun at Time = 0 minutes. Each data point is the mean value (± SD) derived from 3 (CPMM infusions) or 4 (MOC-etomidate infusions) rat experiments. Data for MOC-etomidate infusions were from Reference .

Figure 6

In vitro metabolism of methoxycarbonyl etomidate (MOC-etomidate) and cyclopropyl methoxycarbonyl metomidate (CPMM) in pooled brain tissue from rats. Each data point is the mean value (± SD) from 3 experiments. The lines are nonlinear least squares fits of the data assuming a first-order process with the maxima and minima constrained to 100 and 0, respectively. The metabolic half-lives of MOC-etomidate and CPMM were determined to be 1,414 min (99% confidence interval: 997 – 2,427 min) and 96 min (99% confidence interval: 92 – 101 min), respectively. The same brain tissue homogenate lot was used for all data points.