title: In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning.
abstract: 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 (ICa). Recovery was concentration dependent, with significant ICa recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on ICa 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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Medical Research Building IV, Rm. 1265, 2215B Garland Ave, Nashville, TN, 37232-0575, USA.
authors.forename: Dmytro O
authors.initials: DO
authors.lastname: Kryshtal
authors.affiliation: Department of Pathology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Dawling
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Medical Research Building IV, Rm. 1265, 2215B Garland Ave, Nashville, TN, 37232-0575, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Seger
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Medical Research Building IV, Rm. 1265, 2215B Garland Ave, Nashville, TN, 37232-0575, USA. bjorn.knollmann@vanderbilt.edu.
authors.forename: Bjorn C
authors.identifier: 0000-0003-4956-9735
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D065966:Absorption, Physicochemical; D000818:Animals; D002121:Calcium Channel Blockers / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000506:poisoning; D020013:Calcium Signaling / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control; D002478:Cells, Cultured; D062787:Drug Overdose / Q000097:blood / Q000503:physiopathology / Q000628:therapy; D005217:Fat Emulsions, Intravenous / Q000032:analysis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007022:Hypotension / Q000209:etiology / Q000517:prevention & control; D007700:Kinetics; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D000075082:Proof of Concept Study; D066007:Toxicokinetics; D014280:Triglycerides / Q000032:analysis / Q000097:blood / Q000737:chemistry*; D014700:Verapamil / Q000037:antagonists & inhibitors* / Q000097:blood / Q000494:pharmacology / Q000506:poisoning
chemical_list: D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D014280:Triglycerides; D014700:Verapamil
keywords: Antidote; Lipid emulsion; Lipid sink; Poisoning; Verapamil