Comparative Pharmacokinetics Study of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil Substance and its Solid Dispersion Systems on Rabbits

Introduction. The study of pharmacokinetics of medicinal substances and evaluation of their pharmacokinetic parameters is a necessary stage of pharmaceutical development of original medicinal agents, allowing to choose the composition and dosage form of the preparation. This is due to obtaining characteristics of all processes that occur in the body of an animal (human), from the absorption of a drug from the place of administration to its excretion from the body.
Aim. To conduct a study of the pharmacokinetics of the pharmaceutical substance and the complex compounds based on it to confirm the pharmaceutical development of a drug of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil and to justify the optimal composition of the ready dosage form (GLP).
Materials and methods. The study was carried out on male rabbits with a single oral administration of investigated objects in one dose. Plasma concentrations of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil were determined by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic parameters were calculated by extramodel method of statistical moments.
Results and discussion. Assay 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil quantification in rabbit blood plasma by HPLC has been developed and validated in the concentration range 10–720 ng/ml in accordance with modern requirements and satisfies them for all indicators. Assay was applicated to analysis of plasma samples obtained from laboratory animals after a single oral administration of a substance and solid dispersion systems of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil in one dose. The main pharmacokinetic parameters of the studied objects were calculated after obtained plasma concentrations of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. It was found that the solid dispersion system with Kollidon 17PF has the greatest relative bioavailability from the examined objects; its relative bioavailability to the substance by oral administration was 583 %.
Conclusion. The solid dispersion system method increased the bioavailability of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. Obtained results confirmed correctness of solid dispersion system selection drug e composition and technology development.

1. Novikov M. S., Ivanova O. N., Ivanov A. V., Valuev-Elliston V. T., Temburnikar K., Gurskaya G. V., Kochetkov S. N., Pannecouque C., Balzarini J., Seley-Radtke K. L. 1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents. Bioorganic & Medicinal Chemistry. 2011;19:5794–5902. DOI: 10.1016/j.bmc.2011.08.025.

2. Ozerov A. A., Novikov M. S., Timofeeva Yu. A., Lobachev A. A., Luganchenko A. I., Heisman A. N. Pyrimidine non-nucleoside HIV-1 inhibitors: history of their development and perspectives. Vestnik VolgGMU = Journal of VolgSMU. 2012;3:10–17. (In Russ.)

3. Ozerov A. A., Novikov M. S., Luganchenko A. I., Hartman T., Buckheit R. W. Novel N-[2-(benzoylphenoxy)ethyl] nucleic bases derivatives – synthesis and anti-HIV-1 activity in vitro. Volgogradskij nauchno-medicinskij zhurnal = Volgograd Journal of Medical Research. 2012;4(36):15–18. (In Russ.)

4. Petrov V. I., Novikov M. S., Luganchenko A. I., Ozerov A. A., Rogova N. V. The cluster approach to the creation of biotech drugs. Medicinskaya etika = Medical Ethics. 2014;1:28–31. (In Russ.)

5. Makarov V. G., Makarova M. N., Demchenko D. V. Sposoby povysheniya rastvorimosti lekarstvennogo sredstva na osnove pirimidinovogo proizvodnogo benzofenona [Methods for increasing solubility of medicinal agent based on pyrimidine derivative of benzophenone]. Patent RU № 2729792. 12.08.2020. (In Russ.)

6. Demchenko D. V., Jain (Korsakova) E. A., Balabanyan V. Yu., Makarova M. N., Makarov V. G. Development and biopharmaceutical evaluation of tablets based on the poorly water-soluble substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2020;9(4):79–87. (In Russ.) DOI: 10.33380/2305-2066-2020-9-4-79-87.

7. Mironov A. N., editor. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv [Guidelines for conducting preclinical studies of drugs]. Part one. Moscow: Grif i K; 2013. P. 845–855. (In Russ.)

8. Mironov L. N., editor. Rukovodstvo po ehkspertize lekarstvennyh sredstv [Guidelines for the examination of medicines]. Volume 1. Moscow: Grif i K; 2014. P. 6–44. (In Russ.)

9. Bland M. An Introduction to Medical Statistics (3rd edition). Oxford: Medical Publications; 2000. 422 р.

10. Piotrovskij V. K. Metod statisticheskih momentov i integral’nye model’no nezavisimye parametry farmakokinetiki [Method of statistical moments and integral model independent parameters of pharmacokinetics]. Farmakologiya i toksikologiya. 1986;49(5):118–127. (In Russ.)

11. Zhang Y., Huo M., Zhou J., Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306–314. DOI: 10.1016/j.cmpb.2010.01.007.

12. Kosman V. M., Dzhajn (Korsakova) E. A., Demchenko D. V., Makarov V. G., Balabanyan V. Yu., Standardization of medicinal drug with original substance of benzophenone derivative for HIV-1 infection treatment. Voprosy biologicheskoj, medicinskoj i farmacevticheskoj himii = Problems of Biological, Medical and Pharmaceutical Chemistry. 2021;24(1):4–10. (In Russ.) DOI: 10.29296/25877313-2021-01-01.

13. ICH, Q2A, Harmonized tripartite guideline, text on validation of analytical procedures. IFPMA. In: Proceedings of the International Conference on Harmonization. Geneva. March 1994. P. 1–5.

14. ICH, Q2B, Harmonized tripartite guideline, validation of analytical procedure: methodology. IFPMA. In: Proceedings of the International Conference on Harmonization. Geneva. March 1996. P. 1–8.

15. Guideline on bioanalytical method validation. EMEA/CHMP/EWP192217/2009. London: Committee for medicinal products for human use (CHMP); 2011.

16. Rockville. Guidance for Industry: Bioanalytical method for validation. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, Center for veterinary medicine; 2018.