Investigation of the effects of intravenous lipid emulsion on the pharmacokinetics / toxicokinetics of Ivermectin and Carprofen administered at subtoxic doses

Intravenous lipid emulsion, also called intravenous fat emulsion, is a parenteral nutritional formulation consisting of various vegetable oils, egg phospholipids, water and glycerin. In recent years, it has been used as an effective antidote off-label for treatment in both human and veterinary medicine, especially in the acute toxication of lipophilic drugs and toxic compounds. Although the mechanism of action of intravenous lipid emulsion is not clear, the effect on the kinetic behavior of drugs that cause a toxication has not been fully elucidated. In this study, it was aimed to investigate the effect of intravenous lipid emulsion on the kinetic behavior of ivermectin and carprofen administered intravenously at subtoxic doses. In this study was carried out on 24 clinically healthy and drug-free male New Zealand rabbits with an average weight of 2.78±0.2 kg. 12 rabbits in each group were divided into ivermectin and carprofen groups. In the carprofen group, 6 rabbits were received carprofen alone (12 mg/kg, intravenously) and the other group (6 rabbits) received same dose of carprofen with intravenous lipid emulsion (2.5 ml/kg) as bolus three times at regular intervals. Blood samples were collected 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 16, 24, 32 and 48 hour and 3, 4 and 5 days. In the ivermectin group, 6 rabbits were received ivermectin alone (0.6 mg/kg, intravenously) and the other group (6 rabbits) received same dose of ivermectin with intravenous lipid emulsion (2.5 ml/kg) as bolus three times at regular intervals. Blood samples were collected 0.5, 1, 2, 4, 8, 12, 16, 24, 32 and 48 hour and 3, 4, 5, 6, 7, 8, 10, 15 and 20 days. Drug concentrations in plasma samples were determined by high pressure liquid chromatography. Kinetic parameters were calculated using a non-compartment and three-compartment model for ivermectin, and only a non-compartment model for carprofen. Biochemical analyzes were performed on an autoanalyzer device. No clinical adverse effects were observed in any animals. It was determined that C0 and AUC values in the first 6 hours were significantly higher (P<0.05) and Vdss and Vz values were significantly lower (P<0.05) in the group that was administered intravenous lipid emulsion to the rabbits. Biochemical parameters increased in triglyceride on the 1st day and in ALT and AST levels during the application (P<0.05). It was determined that C0, AUC, MRT and T1/2α values were significantly higher (P<0.05) and Cl, Vz, Vdss, K12 and ClD1-2 values were significantly lower (P<0.05) in the group that was administered intravenous lipid emulsion to the rabbits. Biochemical parameters increased in cholesterol levels was determined on the 2nd day in the group treated with intravenous lipid emulsion (P<0.05). As a result, it was concluded that intravenous lipid emulsion changed the kinetic profile of ivermectin and carprofen in rabbits and the mechanism of action supports the lipid sink theory.