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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. 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. 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. 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.
Bodor,
Recent advances in retrometabolic drug design and targeting approaches.
2000, Pubmed
Bodor,
Recent advances in retrometabolic drug design and targeting approaches.
2000,
Pubmed
Buchwald,
Physicochemical aspects of the enzymatic hydrolysis of carboxylic esters.
2002,
Pubmed
Buchwald,
Structure-metabolism relationships: steric effects and the enzymatic hydrolysis of carboxylic esters.
2001,
Pubmed
Buchwald,
Structure-based estimation of enzymatic hydrolysis rates and its application in computer-aided retrometabolic drug design.
2000,
Pubmed
Campagna,
Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs.
2014,
Pubmed
Cotten,
Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function.
2011,
Pubmed
Cotten,
Methoxycarbonyl-etomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression.
2009,
Pubmed
,
Xenbase
Cotten,
Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.
2010,
Pubmed
,
Xenbase
Flaherty,
Pharmacokinetics of esmolol and ASL-8123 in renal failure.
1989,
Pubmed
Ge,
Electroencephalographic and hypnotic recoveries after brief and prolonged infusions of etomidate and optimized soft etomidate analogs.
2012,
Pubmed
Ge,
Pharmacological studies of methoxycarbonyl etomidate's carboxylic acid metabolite.
2012,
Pubmed
,
Xenbase
Ge,
The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol.
2014,
Pubmed
,
Xenbase
Glass,
Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B).
1993,
Pubmed
Hoke,
Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs.
1997,
Pubmed
Hoke,
Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers.
1997,
Pubmed
Husain,
Modifying methoxycarbonyl etomidate inter-ester spacer optimizes in vitro metabolic stability and in vivo hypnotic potency and duration of action.
2012,
Pubmed
Pejo,
In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.
2012,
Pubmed
,
Xenbase
Pejo,
Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology.
2014,
Pubmed
,
Xenbase
Pejo,
Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats.
2012,
Pubmed
Rosow,
Remifentanil: a unique opioid analgesic.
1993,
Pubmed
Rüsch,
Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.
2004,
Pubmed
,
Xenbase
Shaffer,
Beta-adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol.
1988,
Pubmed
Stańczak,
Prodrugs and soft drugs.
2006,
Pubmed
Sum,
Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite.
1983,
Pubmed
van Ginneken,
Saturable pharmacokinetics in the renal excretion of drugs.
1989,
Pubmed
