Перегляд за Автор "Golovenko, Mykola Ya."

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    Nhibition of cytochrome p450 activities by propoxazepam: safety assessment in context for potential drug interactions
    (Igor Sikorsky Kyiv Polytechnic Institute, 2025) Larionov, Vitalii B.; Golovenko, Mykola Ya.; Valivodz, Iryna P.; Reder, Anatoliy S.
    Background.Propoxazepam is a new anelgetic agent of the benzodiazepine group, chemically known as 7-bromo-5-(o-chlorophenyl)-3-propyloxy-1,2-dihydro-3H-1,4-benzodiazepine-2-one. Propoxazepam is con-sidered a possible substrate of the CYP system, so its effect of on the CYP3A4 enzyme activity was investi-gated in vitrousing human liver microsomes.Objective.To evaluate the effects of propoxazepam on CYP3A4 activity in vitrousing testosterone and mida-zolam as markers of metabolic activity for CYP3A4 in human liver microsomes.Methods.Midazolam (1-hydroxylation reaction) and testosterone (6-hydroxylation reaction) were used as markers for CYP3A4-mediated activity. Ketoconazole (0.2 M) was used as a positive control for reversibleinhibition, and troleandomycin (50 M) for metabolism-dependent inhibition. For reversible inhibition, pro-poxazepam was added together with the corresponding substrate and cofactor (NADPH), while for metabo-lism-dependent inhibition, it was incubated with microsomes and cofactor for 30 minutes prior to substrate addition.Results.Propoxazepam at various concentrations (0 to 100 M) consistently inhibited CYP3A4 activities for both substrates, showing a similar "concentration–activity inhibition" dependence, with IC50values of 52.34.9M for midazolam and 46.1 9.2 M for testosterone. For metabolism-dependent inhibition, IC50values were 36.6 8.6 M for midazolam and 28.3 7.4 M for testosterone. Given that the binding of pro-poxazepam to microsomal protein under the experimental conditions, which reflected those in the IC50ex-periments, was low, no microsomal binding correction factor was applied to the reported IC50values.Conclusions.The highest predicted unbound Cmaxplasma concentration of propoxazepam, above which in-teractions can occur, is between 0.462 and 0.524 M, or 462 and 524 nM. This corresponds to concentra-tions of 188 to 214ng/mL (based on the molecular weight of propoxazepam, 414.73g/mol). According to pharmacokinetic data, these concentrations are not achievable after a single oral administration. Furtherstudies are required for multiple-dose administration.