Pharmacokinetics of a new antiplatelet agent, an indolinone derivative in the experiment

Abstract

   Introduction. More than 18 million people die every year from complications (the most common of them are thrombosis of the cerebral, coronary and peripheral vessels) caused by diseases of the cardiovascular system. Optimal prevention of thrombosis (antiplatelet therapy) requires the use of drugs that would be able to eff ectively prevent thrombus formation without increasing the risk of bleeding. A new indolinone derivative (codenamed GRS) has potent antiaggregant action and low toxicity (LD 50 for rats > 5000 mg/kg). However, selecting the effective dose and dosage regimen for GRS requires data on its pharmacokinetics in oral and intravenous administration.
   Aim. To determine the pharmacokinetics of a new antiplatelet agent, an indolinone derivative (GRS) after a single intravenous and oral administration to rats.
   Materials and methods. The GRS compound was administered as a 1 mg/kg aqueous solution into the tail vein or as a 10 mg/kg suspension in carboxymethyl cellulose aqueous solution for oral (intragastrical) administration. Blood samples were taken at 5, 10, 20, 40 min, 1, 2, 4, and 8 h, and urine samples were collected at 2, 4, 8, 12, and 24 h after administration. GRS was detected in biological samples using high-performance liquid chromatography with ultraviolet detection.
   Results. The study has demonstrated that with both routes of administration, the antiaggregant eff ect of GRS lasts for at least 8 hours, being lipohpilic, GRS is rapidly distributed in organs and tissues by passive diffusion, undergoes biotrans-formation and is excreted in the urine mostly as metabolites, since at most 2.5 % of the initial compound is excreted in the urine. Bioavailability of GRS does not exceed 12 %.
   Conclusion. After intravenous and oral administration to rats, the GRS compound is excreted in the urine mostly as metabolites; metabolic clearance is more prominent after GRS oral administration.