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Investigation of the pharmacokinetics of an original drug for the treatment of HIV-1 infection


V.M. Kosman(1); D.V. Demchenko(1), E.A. Jain (Korsakova)(2), V.G. Makarov(3); V.Yu. Balabaniyan(2) 1-Saint Petersburg Institute of Pharmacy, 3, Zavodskaya St., Build. 245, Kuzmolovsky Urban-Type Community, Vsevolozhsky District, Leningrad Region 188663, Russian Federation; 2-M.V. Lomonosov Moscow State University, 27, Lomonosovsky Prospect, Build. 1, Moscow 119991, Russian Federation; 3-PHARMACY HOUSE Research and Production Association, 3, Zavodskaya St., Build. 245, Kuzmolovsky Urban-Type Community, Vsevolozhsky District, Leningrad Region 188663, Russian Federation

Introduction. HIV-1 infections have been proposed to be treated with the original drug 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil as tablets. The necessary stage of preclinical trials of the original drug is to investigate its pharmacokinetics. Objective: to evaluate the pharmacokinetics of the drug based on the benzophenone derivative of pyrimidine for the treatment of HIV-1 infection in two animal species. Material and methods. The investigation was conducted with sexually mature male rats and rabbits after single intragastric administration (in rats), oral administration as three doses (in rabbits), and multiple administration as two doses to the rats. The concentrations of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil in plasma, tissues, organs, and feces were determined by high-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) detection. The pharmacokinetic parameters were calculated by the extramodel method of statistical moments. Results. The authors’ previously developed procedure for the quantitative determination of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil in rabbit plasma is adapted for the analysis of rat plasma, tissues and organs (for example, the liver). It was found that the pharmacokinetics of the test drug was nonlinear in the dose range of 20–100 mg/kg for rats and 10–50 mg/kg for rabbits. The time to maximum concentration (Tmax) was about 5–6 h; the mean retention time (MRT) was about 30–50 h for rats and about 16–17 h for rabbits; the half-life (T1/2) was about 31–36 h for rats and about 11–13 h for rabbits. Comparison of the data obtained for two biological species (rats and rabbits) revealed the higher values of a number of pharmacokinetic parameters (Cmax and AUC0-48, MRT and T1/2) for rats, which could indicate the species-specific pharmacokinetics of the test drug. Repeated administration of the drug at the doses of 60 and 100 mg/kg to the rats for 3 days did not result in the accumulation of an active ingredient. The active ingredient was distributed to the highly vascularized organs responsible for excretion, such as the liver and kidneys. The supply of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil to the heart and spleen, as well as the ability of the analyzed compound to penetrate the blood-brain barrier and to enter the brain have not been established. About 9% of the active ingredient was excreted unchanged in the feces; no analyte was detected in the urine. Conclusion. Pharmacokinetic parameters of original drug were evaluated. The procedures are validated in accordance with the present-day requirements.

oral administration
tissues and organs

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