An in vitro study to determine the impact of lipid emulsion on partitioning of a broad spectrum of drugs associated with overdose

Background

Intravenous lipid emulsion is recognised as a therapy for rescue in cases of local anaesthetic toxicity, but its use in reversing overdose or toxicity related to other drugs remains the subject of debate. This in vitro study sought to expand our understanding of the importance of partitioning in determining the impact of intravenous lipid emulsion on aqueous free drug concentrations.

Methods

Twenty-seven drugs and associated metabolites were screened for the ability of intravenous lipid emulsion to reduce the amount of free drug in the aqueous phase, using specialised cassettes designed for this purpose. The relative amount of drug equilibrating across the membrane from plasma to phosphate-buffered saline was measured, using liquid chromatography–mass spectrometry, at a 6 h timepoint in plasma samples treated with intravenous lipid emulsion and paired, untreated controls.

Results

The data obtained were plotted against measures of partition (LogP and cLogD_7.4) and with log-transformed non-protein bound drug. There were significant inverse correlations between the capacity for intravenous lipid emulsion to reduce drug detected in the phosphate-buffered saline compartment and LogP and cLogD_7.4, and a direct association with log [non-protein-bound drug]. However, a number of drugs showed substantial variance between different plasma samples.

Conclusions

Modulation of free drug in the aqueous compartment is broadly predictable by the partition coefficient, although ramipril was identified to be an outlier in this regard. Further mechanistic and clinical exploration is merited to establish a standardised protocol for lipid emulsion therapy.