Lipid emulsion in blood increases extraction of amitriptyline in liposome augmented peritoneal dialysis in rats chronically dosed with amitriptyline: could nanoparticles mitigate the limitations to dialysis in intoxication?

Abstract

Background: The reach of dialysis in toxicology is limited by two factors, high toxicant volume of distribution and low dialytic extraction of protein bound toxicants in blood. Therapeutic actions for lipid emulsion as antidote are thought involve a "lipid shuttle", whereby lipid droplets in the circulation "shuttle" lipophilic toxicants with "boarding" in well perfused heart and brain tissue with high toxicant concentrations and "exit" to biologically inert slower equilibrating sites such as muscle or adipose where toxicant concentrations are lower. Such a mechanism raises the conceptual possibility of an extracorporeal "exit" potentially mitigating toxicity through increased drug clearance. In experimental models drug binding nanoparticles in dialysate have been shown to mitigate the problem of blood proteins binding toxicant. We investigated whether the addition of intravenous lipid emulsion would increase extraction of amitriptyline into nanoparticle augmented peritoneal dialysate in rats orally dosed with amitriptyline for 1 week.

Methods: Rats were dosed with amitriptyline in drinking water for a week. On the day of the experiment, anaesthetised rats received either an initial bolus then infusion of lipid emulsion for one hour, or a bolus of saline at the initiation of the experiment equal to the total volume of lipid emulsion given. After a 50 min equilibration period, a 10 min pH gradient nanoparticle augmented peritoneal dialysis dwell was undertaken. Animals were humanely euthanised at the end of the experiment. Blood was sampled 0, 10, 45 and 60 min and peritoneal dialysate was analysed for amitriptyline concentration.

Results: There were no significant differences in baseline physiology, initial amitriptyline blood concentration, nor pulse and blood pressure at any time between groups. Time weighted individual subject mean blood amitriptyline concentrations (median (IQR)); control 104 (87-125) nmol/l, lipid 219 (148-357) nmol/L, p = 0.03 and dialysate amitriptyline concentration; control 31(14-52) nmol/L, lipid 105 (62-185) nmol/L, p = 0.03 were greater in animals given intravenous lipid emulsion.

Conclusion: These are the first data to our knowledge showing experimental support for the approach of simultaneously decreasing volume of distribution with an intravascular nanoparticle in conjunction with a drug binding particle in dialysate. Further work in this area is warranted.