In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

• Published in: Journal of medical toxicology Vol. 12; no. 2; pp. 165 - 171
• Main Authors: Kryshtal, Dmytro O., Dawling, Sheila, Seger, Donna, Knollmann, Bjorn C.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2016; Springer Nature B.V
• Subjects: Absorption, Physicochemical; Animals; Biomedical and Life Sciences; Biomedicine; Calcium (intracellular); Calcium Channel Blockers - blood; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - poisoning; Calcium channels (L-type); Calcium currents; Calcium ions; Calcium Signaling - drug effects; Cardiac muscle; Cardiotoxicity - etiology; Cardiotoxicity - prevention & control; Case reports; Cells, Cultured; Contractility; Drug Overdose - blood; Drug Overdose - physiopathology; Drug Overdose - therapy; Drug therapy; Fat Emulsions, Intravenous - analysis; Fat Emulsions, Intravenous - chemistry; Fat Emulsions, Intravenous - therapeutic use; Heart; Humans; Hydrophobic and Hydrophilic Interactions; Hypotension; Hypotension - etiology; Hypotension - prevention & control; Infusion; Intracellular; Intravenous administration; Kinetics; Lipids; Lipophilic; Mice, Inbred C57BL; Myocardial Contraction - drug effects; Myocytes; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Nutrition; Original; Original Article; Parenteral nutrition; Patch-Clamp Techniques; Pharmacology/Toxicology; Phospholipids; Poisoning; Prescription drugs; Proof of Concept Study; Recovery; Soybeans; Toxicokinetics; Triglycerides - analysis; Triglycerides - blood; Triglycerides - chemistry; Ventricle; Verapamil; Verapamil - antagonists & inhibitors; Verapamil - blood; Verapamil - pharmacology; Verapamil - poisoning; Verapamil; Poisoning; Lipid emulsion; Lipid sink; Antidote
• ISSN: 1556-9039; 1937-6995
• DOI: 10.1007/s13181-015-0511-y

Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte l -type Ca 2+ currents, intracellular Ca 2+ , and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/MS verapamil assays showed that addition of ILE (0.03–5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode’s solution containing 5 μM verapamil recovered l -type Ca 2+ currents (I Ca ). Recovery was concentration dependent, with significant I Ca recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on I Ca in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca 2+ . Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.