The Effects of Modifying In Vivo Cytochrome P450 3A (CYP3A) Activity on Etoricoxib Pharmacokinetics and of Etoricoxib Administration on CYP3A Activity

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin <i>N</i>-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.

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Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein

British Journal of Clinical Pharmacology ◽

10.1111/j.1365-2125.2005.02343.x ◽

2005 ◽

Vol 59 (4) ◽

pp. 440-446 ◽

Cited By ~ 19

Author(s):

A. G. Pinto ◽

J. Horlander ◽

N. Chalasani ◽

M. Hamman ◽

A. Asghar ◽

...

Keyword(s):

Cytochrome P450 ◽

Cyp3a Activity ◽

Cytochrome P450 3A

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In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000268 ◽

2016 ◽

Vol 38 (2) ◽

pp. 230-238 ◽

Cited By ~ 9

Author(s):

Karin Skoglund ◽

Johan Richter ◽

Ulla Olsson-Strömberg ◽

Jonas Bergquist ◽

Warunika Aluthgedara ◽

...

Keyword(s):

Cytochrome P450 ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Therapeutic Outcome ◽

Cytochrome P450 3A

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

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0036 ◽

2018 ◽

Vol 33 (2) ◽

pp. 65-73 ◽

Cited By ~ 6

Author(s):

Dmitriy V. Ivashchenko ◽

Anastasia V. Rudik ◽

Andrey A. Poloznikov ◽

Sergey V. Nikulin ◽

Valeriy V. Smirnov ◽

...

Keyword(s):

Cell Culture ◽

Cytochrome P450 ◽

In Silico ◽

In Vivo Studies ◽

Cyp3a Activity ◽

Cell Culture Study ◽

Study Results ◽

Three Stages

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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