title: Pharmacological studies of methoxycarbonyl etomidate's carboxylic acid metabolite.
abstract: 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 γ-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 α(1)(L264T)β(2)γ(2L) GABA(A) 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 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 μM 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 μM for MOC-etomidate. The half-maximal inhibitory concentration 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 3 biological assays, MOC-ECA's potency was approximately 300-fold lower than that of MOC-etomidate.
authors: Department of Anesthesia, Critical Care, and Pain Medicine, 55 Fruit St., Boston, MA 02114-2621, USA.
authors: Ri Le
authors: RL
authors: Ge
authors: Ervin
authors: E
authors: Pejo
authors: Marian
authors: M
authors: Haburcak
authors: S Shaukat
authors: SS
authors: Husain
authors: Stuart A
authors: SA
authors: Forman
authors: Douglas E
authors: DE
authors: Raines
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002264:Carboxylic Acids / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology*; D007814:Larva; D008564:Membrane Potentials; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D002264:Carboxylic Acids; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; C543057:methoxycarbonyletomidate; D006854:Hydrocortisone; D005045:Etomidate