Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies
Abstract 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 phenazep...
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Published in | Drug metabolism and drug interactions Vol. 33; no. 2; pp. 65 - 73 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin
De Gruyter
27.06.2018
Walter de Gruyter GmbH |
Subjects | |
Online Access | Get full text |
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Summary: | Abstract
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. |
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ISSN: | 2363-8907 0792-5077 2363-8915 2191-0162 |
DOI: | 10.1515/dmpt-2017-0036 |