title: 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.
authors.affiliation: From the *Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and †Aberjona Laboratories, Woburn, Massachusetts.
authors.forename: Ervin
authors.initials: E
authors.lastname: Pejo
authors.forename: Jifeng
authors.initials: J
authors.lastname: Liu
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Lin
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Raines
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005045:Etomidate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000378:metabolism*; D007814:Larva; D051381:Rats; D017207:Rats, Sprague-Dawley; D014982:Xenopus laevis
chemical_list: D006993:Hypnotics and Sedatives; C543057:methoxycarbonyletomidate; C084586:metomidate; D005045:Etomidate