Investigation of pharmacokinetics of N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide various crystalline modifications in vivo

  • P. S. Bondarenko National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • N. I. Voloshchuk National Pirogov Memorial Medical University, Vinnytsya, Ukraine
  • V. B. Larionov A.V. Bogatsky Physico-Chemical Institute National Academy of Sciences of Ukraine, Odesa, Ukraine
  • H. О. Fedoseenko ALC «Interhim», Odesa, Ukraine
Keywords: N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide, polymorphic modifications, crystal habitus, parameters of pharmacokinetic.

Abstract

The phenomenon of polymorphism, inherent in many biologically active substances, including drugs, is an extremely serious problem that requires close attention and comprehensive study. Various crystalline modifications of biologically active compounds, as well as excipients can dramatically change the biopharmaceutical properties and pharmacological characteristics of already known drugs. The bioactive compound N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide was obtained by bioisosterical substitution in the molecule of known non-steroidal anti-inflammatory drugs of the oxycam group in the form of three polymorphic modifications of the crystal. sticks (form A), plates (form B) and blocks (form C) with varying degrees of analgesic and anti-inflammatory effects. The aim of the study was to investigate the pharmacokinetic profile of these polymorphic forms of benzothiazine-3-carboxamide derivative by their oral administration in vivo. The concentration of compounds in the blood of mice was determined by HPLC and the main pharmacokinetic parameters were calculated. It was found that the polymorphic form in the form of plates (form B), in particular, having the largest surface area of crystals, has differences mainly at the stage of absorption with corresponding changes in absorption values, maximum concentration and time of its achievement, has the highest bioavailability and rapid elimination which correlates with the most optimal pharmacological and toxicological characteristics of this compound in comparison with other crystalline forms. This makes it possible to recommend the most active and safe polymorphic form of the compound (form B) for in-depth preclinical study and possible clinical trials as an analgesic and anti-inflammatory agent.

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Published
2020-12-28
How to Cite
Bondarenko, P. S., Voloshchuk, N. I., Larionov, V. B., & Fedoseenko H. О. (2020). Investigation of pharmacokinetics of N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide various crystalline modifications in vivo. Biomedical and Biosocial Anthropology, (41), 46-51. https://doi.org/10.31393/bba41-2020-08