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Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs.

Anesthesiology (2014-08-30)
Jason A Campagna, Kevin Pojasek, David Grayzel, John Randle, Douglas E Raines
ABSTRACT

Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. Compared with etomidate, CPMM was half as potent as a hypnotic (ED50 approximately 0.8 mg/kg), was more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 vs. 1,623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. The studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
Sigma-Aldrich
Hydrocortisone, γ-irradiated, powder, BioXtra, suitable for cell culture
Supelco
Hydrocortisone, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
2,6-Diisopropylphenol, 97%
USP
Hydrocortisone, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Hydrocortisone, meets USP testing specifications
Hydrocortisone for peak identification, European Pharmacopoeia (EP) Reference Standard
Supelco
Propofol solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Propofol, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Etomidate, >98% (HPLC), powder
Hydrocortisone, European Pharmacopoeia (EP) Reference Standard
Supelco
2,6-Diisopropylphenol, analytical standard
Propofol for peak identification, European Pharmacopoeia (EP) Reference Standard
Hydrocortisone, British Pharmacopoeia (BP) Assay Standard
Supelco
Hydrocortisone, VETRANAL®, analytical standard
Etomidate impurity B, European Pharmacopoeia (EP) Reference Standard