Pharmacokinetics and tissue distribution of 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d] pyrimidine-6-carboxamide, an allosteric agonist of the luteinizing hormone receptor, during ovulation induction in immature female rats

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Gonadotropins are widely used clinically for controlled ovulation induction, but they have a number of serious side effects, including ovarian hyperstimulation. Low-molecular-weight allosteric agonists of the luteinizing hormone (LH) receptor, including our newly developed compound 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido) phenyl)thieno[2,3-d]-pyrimidine-6-carboxamide (TP03), may be an alternative. However, their pharmacokinetics and tissue distribution remain largely unstudied. Aim of the study was to investigate the dynamics of changes in TP03 blood levels during its use to induce ovulation in immature female rats stimulated with follimag, as well as to evaluate TP03 distribution in the ovaries and liver of the animals. Material and methods. Immature female rats stimulated with follimag were administered with TP03 (15 mg/kg, intraperitoneally). Blood estradiol and progesterone levels, as well as the number of preovulatory follicles and corpora lutea in the ovaries, were then assessed over 24 hours. TP03 levels in plasma, ovaries, and liver were measured using reversed-phase HPLC with tandem mass spectrometry. Results. TP03 increased blood progesterone content (peaking at 8 hours) and resulted in corpora lutea formation after 16–24 hours. TP03 was detectable in plasma for 24 hours, reaching its maximum concentration (Cmax, 3530 ng/ml) 0.25 hours (Tmax) after administration, indicating rapid absorption of the compound. The half-life (t1/2) of TP03 was 3.11 hours, and the mean residence time (MRT) in the body was 4.29 hours. TP03 accumulation in the ovaries and liver was demonstrated as early as 1 hour after administration. Conclusions. TP03 stimulates the LH receptor, increases progesterone production, and induces ovulation in immature female rats. Its high effectiveness as an ovulation inducer is largely due to its rapid entry into the bloodstream and effective absorption in the ovaries.

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