Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid.

Abstract

The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (~10× clinical) ABP-700 doses. γ-aminobutyric acid type A (GABAA) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg · kg(-1) · min(-1), 1.5 mg · kg(-1) · min(-1), or 2.3 mg · kg(-1) · min(-1)). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed α1β3γ2L GABAA and α1β glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 μM, 45 μM, and 102 μM (ABP-700) and 282 μM, 478 μM, and 1,110 μM (CPM-acid). ABP-700 and CPM-acid concentration-GABAA receptor response curves defined using 6 μM γ-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM γ-aminobutyric acid were 770 μM (95% CI, 590 to 1,010 μM) and 1,450 μM (95% CI, 1,340 to 1,560 μM), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 μM (95% CI, 1,240 to 1,330 μM). High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms. CPM-acid inhibits both GABAA and glycine receptors at the high (~100× clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.