In vitro studies of detoxification by intravenous fat emulsions: mechanism of action and preclinical assessment tools

Abstract

Introduction The use of intravenous fat emulsions for treatment of drug intoxication still follows a trial-and-error approach, due to insufficient understanding of the mechanisms of the process and lack of predictive in vitro tools.Methods We studied the physicochemical mechanisms of drug extraction from model plasma for seven drugs (bromazepam, bupivacaine, diphenhydramine, mepivacaine, quetiapine, paracetamol and verapamil) with clinical data for the detoxification efficiency of intravenous fat emulsions. Five of the studied drugs were labeled as “responders,” due to clinical reports of successful patient detoxification, whereas the other two drugs were “non-responders,” as they did not respond to intravenous fat emulsion treatment.Results For all responders, drug extraction increased significantly with the increase of emulsion concentration, while the drug partition coefficient between model plasma and intravenous fat emulsion (Intralipid®) remained around or above 10: viz. the concentration of drug in the lipid phase was ten‑fold higher than in its concentration in the model plasma.Discussion Drug partitioning from the model plasma to the bulk of the emulsion oil droplets was identified as the primary scavenging mechanism, whereas adsorption on the oil-water interface did not influence the process. For the studied seven drugs, it was established that a threshold value of 10 of the drug partition coefficient between model plasma and intravenous lipid emulsion can be successfully used to discriminate between drugs for which intravenous fat emulsions can lead to partitioning, indicating potential clinical efficiency in detoxification.Conclusion The approach described can be used to guide clinical practice in drug intoxication cases where a specific antidote is not available, expanding the treatment options of patients in intensive care conditions.