Evaluation of the pharmacokinetics, chylomicron inhibition, and toxicity of colchicine in rats given low doses

Abstract

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.