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Background:  Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam’s metabolic liver pathways and other pharmacokinetic features.    Methods:  To determine phenazepam’s metabolic pathways, the study was divided into three stages:  in silico  modeling,  in vitro  experiment (cell culture study), and  in vivo  confirmation.  In silico  modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The  in vitro  study was performed using a hepatocytes’ cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam’s metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients.    Results:  According to  in silico  and  in vitro  analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the  in vivo  study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94–4.65] to 2.79 [95% CI: 2.02–3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam.    Conclusions:  Experimental  in silico  and  in vivo  studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

Which cytochrome P450 metabolizes phenazepam? Step by step in silico , in vitro , and in vivo studies