Perioperative Medicine  |   August 2019
Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid
Author Notes
  • From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (B.I.V., M.M., J.J.A.M., D.E.R.); the University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Groningen, The Netherlands (B.I.V.); R&D Consulting, Terrebonne, Quebec, Canada (D.L.); and The Medicines Company, Parsippany, New Jersey (B.Z.).
  • This work was presented in part at the 27th Annual Meeting of the International Society of Anesthetic Pharmacology, in San Francisco, California on October 12, 2018.
    This work was presented in part at the 27th Annual Meeting of the International Society of Anesthetic Pharmacology, in San Francisco, California on October 12, 2018.×
  • Submitted for publication November 9, 2018. Accepted for publication March 26, 2019.
    Submitted for publication November 9, 2018. Accepted for publication March 26, 2019.×
  • Address correspondence to Dr. Raines: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB444, Boston, Massachusetts 02114. draines@partners.org. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   August 2019
Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid
Anesthesiology 8 2019, Vol.131, 287-304. doi:10.1097/ALN.0000000000002758
Anesthesiology 8 2019, Vol.131, 287-304. doi:10.1097/ALN.0000000000002758
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The investigational etomidate analog ABP-700 causes involuntary muscle movements in humans at anesthetic doses and seizures in dogs at 10-fold higher toxicologic doses

  • The mechanism of seizures in dogs, and their relationship to involuntary muscle movements in humans, is unknown

What This Article Tells Us That Is New:

  • Toxicologic studies in dogs using supratherapeutic ABP-700 doses caused involuntary muscle movements and seizures, but these were temporally and electroencephalographically distinct, suggesting different underlying mechanisms

  • Events occurred at ABP-700 and metabolite concentrations one and two orders of magnitude higher, respectively, than those found in humans

  • Electrophysiologic studies of the principal metabolite of ABP-700 in oocyte-expressed γ-aminobutyric acid type A receptors showed inhibition at the high supratherapeutic concentrations achieved in the dogs, and such inhibition may explain seizure activity

  • Proepileptiform effects of ABP-700 in dogs may not be relevant to humans at therapeutic doses

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.