Evaluation of mean arterial blood pressure, heart rate, and sympathetic nerve activity in rabbits after administration of two formulations of etomidate.
OBJECTIVE
To evaluate and compare the effects of the aqueous sulfobutyl ether beta-cyclodextrin (SBE-CD) etomidate formulation and the commercial etomidate formulation on mean arterial pressure (MAP), heart rate, and sympathetic outflow using neuraxis-intact and baro-denervated rabbits.


METHODS
Prospective experimental study.


METHODS
Twenty-seven male New Zealand white rabbits.


METHODS
Under basal anesthesia (urethane) and ventilation with intermittent positive pressure (IPPV), the New Zealand white rabbits underwent surgical preparation including isolation of the left renal sympathetic nerve and, in the baro-denervated models, additional combined denervation of bilateral carotid sinus, aortic, and vagal nerves. After hemodynamic stabilization, both neuraxis-intact and baro-denervated animals received bolus intravenous (IV) injection (0.6 mg kg(-1)) of either the SBE-CD or commercial etomidate formulation over 5 seconds (n = 6 animals per group).


RESULTS
Mean arterial pressure decreased significantly in all four groups to the same extent. However, the rate of MAP decrease was lower in the SBE-CD-treated groups relative to the commercial formulation. Renal sympathetic nerve activity was decreased significantly less in the SBE-CD group in the baro-denervated studies. Independent pharmacokinetic evaluation demonstrated that the two formulations had comparable plasma concentration-time profiles.


CONCLUSIONS
Etomidate in the commercial drug product is solubilized with propylene glycol, a cosolvent associated with adverse side effects on injection. An aqueous formulation of etomidate has been developed, which utilizes SBE-CD as a solubilizing agent. The data suggest that the SBE-CD etomidate formulation may be a safer IV induction formulation than the commercial etomidate drug product.
McIntosh
Michelle P
MP
The Center for Drug Delivery Research, The University of Kansas, Lawrence, KS, USA. mmcintosh@ku.edu
Narita
Hideyuki
H
Kameyama
Yoshiyuki
Y
Rajewski
Roger A
RA
Goto
Hiroshi
H
D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects*; D005045:Etomidate / Q000493:pharmacokinetics / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D019946:Propylene Glycol / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D011817:Rabbits / Q000502:physiology*; D011897:Random Allocation; D012995:Solubility; D012997:Solvents / Q000008:administration & dosage / Q000009:adverse effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects
D006993:Hypnotics and Sedatives; D012997:Solvents; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D019946:Propylene Glycol; D005045:Etomidate