PHARMACOKINETIC MECHANISMS UNDERLYING DIFFERENCESIN THE BIOLOGICAL ACTIVITY OF POLYMORPHIC FORMSOF ETHYL 4-METHYL-2,2-DIOXO-1H-2λ6,1-BENZOTHIAZINE-3-CARBOXYLATE

Introduction. The study investigated the relationship between crystal structure, pharmacokinetic parameters, and pharmacodynamic activity of polymorphic modifications of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine- 3-carboxylate. The relevance of the study is associated with the need to develop new non-steroidal antiinflammatory drugs with improved efficacy and safety profiles. In this regard, derivatives of 1H-2λ6,1-benzothiazine are of particular interest, as pronounced analgesic and anti-inflammatory properties have previously been demonstrated for compounds of this class. The aim of the study was to establish the relationship between crystal structure, pharmacokinetic parameters, and pharmacodynamic activity of polymorphic modifications of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine- 3-carboxylate. Research Methods. The objects of the study were two polymorphic forms of ethyl 4-methyl-2,2-dioxo-1H- 2λ6,1-benzothiazine-3-carboxylate: the monoclinic form NI-75 and the orthorhombic form NI-77. Pharmacodynamic studies were performed using a carrageenan-induced inflammatory hyperalgesia and exudative reaction model in rats. Pharmacokinetic parameters were determined after single oral administration of the compounds to mice at a dose of 10 mg/kg using HPLC-MS analysis. The main pharmacokinetic parameters were calculated from concentration-time curves using non-compartmental analysis. Results and Discussion. It was found that polymorphic modifications of the same compound differed significantly in pharmacological activity. The monoclinic form NI-75 exhibited markedly higher anti-exudative and analgesic activity compared with the orthorhombic form NI-77 and exceeded the efficacy of the reference drugs meloxicam and piroxicam. Pharmacokinetic analysis demonstrated that the major differences between the polymorphic forms were associated with the absorption stage. The monoclinic form was characterized by significantly higher absorption rate constant values, maximum plasma concentration, area under the pharmacokinetic curve, and bioavailability. At the same time, elimination and distribution parameters of both polymorphs did not differ significantly, indicating similar behavior of the compound after entering the systemic circulation. The pharmacokinetic features were shown to correlate with X-ray crystallographic data. The denser molecular packing of the orthorhombic form probably complicates crystal lattice disruption and slows dissolution and absorption of the compound. In contrast, weaker intermolecular interactions in the monoclinic form may facilitate faster release and systemic absorption of the substance. Conclusions. The obtained results demonstrate the important role of polymorphism in the formation of pharmacokinetic and pharmacodynamic properties of 1H-2λ6,1-benzothiazine derivatives and open prospects for the targeted search for new biologically active polymorphic modifications with optimized pharmacological characteristics.