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01-11-2020 | Tenofovir | Original Article

In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine

Authors: Anand Joshi, Brian F. Kiesel, Nupur Chaphekar, Reyna Jones, Jianxia Guo, Charles A. Kunos, Sarah Taylor, Edward Chu, Raman Venkataramanan, Jan H. Beumer

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2020

Abstract

Purpose

To investigate the metabolic pathways of triapine in primary cultures of human hepatocytes and human hepatic subcellular fractions; to investigate interactions of triapine with tenofovir and emtricitabine; and to evaluate triapine as a perpetrator of drug interactions. The results will better inform future clinical studies of triapine, a radiation sensitizer currently being studied in a phase III study.

Methods

Triapine was incubated with human hepatocytes and subcellular fractions in the presence of a number of inhibitors of drug metabolizing enzymes. Triapine depletion was monitored by LC–MS/MS. Tenofovir and emtricitabine were co-incubated with triapine in primary cultures of human hepatocytes. Triapine was incubated with a CYP probe cocktail and human liver microsomes, followed by LC–MS/MS monitoring of CYP specific metabolite formation.

Results

Triapine was not metabolized by FMO, AO/XO, MAO-A/B, or NAT-1/2, but was metabolized by CYP450s. CYP1A2 accounted for most of the depletion of triapine. Tenofovir and emtricitabine did not alter triapine depletion. Triapine reduced CYP1A2 activity and increased CYP2C19 activity.

Conclusion

CYP1A2 metabolism is the major metabolic pathway for triapine. Triapine may be evaluated in cancer patients in the setting of HIV with emtricitabine or tenofovir treatment. Confirmatory clinical trials may further define the in vivo triapine metabolic fate and quantify any drug–drug interactions.

Available only for authorised users

https://clinicaltrials.gov/ct2/results?cond=&term=triapine&cntry=&state=&city=&dist (Accessed October 4th 2019).

https://www.absorption.com/wp-content/uploads/2014/07/Substrate+Specificity+for+FMO-+and+CYP-Mediated+Reactions+and+Enzyme+Inactivation+in+HLM_+Methyl-p-Tolyl+Sulfide+versus+Benzydamine.pdf (Accessed 10/06/2019).

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Title: In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine
Authors: Anand Joshi
Brian F. Kiesel
Nupur Chaphekar
Reyna Jones
Jianxia Guo
Charles A. Kunos
Sarah Taylor
Edward Chu
Raman Venkataramanan
Jan H. Beumer
Publication date: 01-11-2020
Publisher: Springer Berlin Heidelberg
Keywords: Tenofovir
Ketoconazole
Methimazole
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04154-5

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