Nhibition of cytochrome p450 activities by propoxazepam: safety assessment in context for potential drug interactions
Вантажиться...
Дата
2025
Науковий керівник
Назва журналу
Номер ISSN
Назва тому
Видавець
Igor Sikorsky Kyiv Polytechnic Institute
Анотація
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 52.34.9M 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.
Опис
Ключові слова
propoxazepam, CYP3A4, testosterone, midazolam, reversible inhibition, metabolism dependent inhibition, пропоксазепам, тестостерон, мідазолам, оборотне інгібування, залежне від метаболізму інгібування
Бібліографічний опис
Nhibition of cytochrome p450 activities by propoxazepam: safety assessment in context for potential drug interactions / V. B. Larionov, M. Ya. Golovenko, I. P. Valivodz, A. S. Reder // Innovative Biosystems and Bioengineering : international scientific journal. – 2025. – Vol. 9, No. 2. – P. 4-11. – Bibliogr.: 28 ref.