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

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutics and Biopharmaceutics Pub Date : 2024-07-06 DOI:10.1016/j.ejpb.2024.114392
Hamdah M. Al Nebaihi, Neal M. Davies, Dion R. Brocks
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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.

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评估小剂量大鼠体内秋水仙碱的药代动力学、乳糜泻抑制作用和毒性。
秋水仙碱(COL)以其抑制肠道乳糜微粒形成的能力而闻名,并已被用作一种非手术工具来探索通过肠道淋巴管吸收药物的情况。然而,人们对它的药代动力学及其与所用剂量的效果和毒性的关系了解有限。本研究旨在提供全面的 COL 药代动力学数据,并将其与低剂量的淋巴阻断和毒性效应相关联。雄性 Sprague-Dawley 大鼠颈静脉插管(JVC),通过口服、0.25 毫克/千克腹腔注射和 0.1 毫克/千克静脉注射等途径接受 0.1 至 0.5 毫克/千克 COL,然后抽取血液和尿液进行 LC-MS/MS 分析。另外 8 只 JVC 大鼠接受了含 COL 和不含 COL 的花生油,随后进行了血液药代动力学和血浆生化分析,评估了对脂质吸收的影响。结果显示,COL 的总清除率和分布容积较高,而口服生物利用度较低 (
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来源期刊
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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