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

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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.

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Notes

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

  2. 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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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Anand Joshi, Brian F. Kiesel, Nupur Chaphekar, Sarah Taylor, Raman Venkataramanan & Jan H. Beumer

  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Brian F. Kiesel, Reyna Jones, Jianxia Guo, Edward Chu & Jan H. Beumer

  3. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Charles A. Kunos

  4. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Pittsburgh-Magee Women’s Hospital, Pittsburgh, PA, USA

    Sarah Taylor

  5. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Edward Chu & Jan H. Beumer

  6. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Raman Venkataramanan

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  1. Anand Joshi
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Joshi, A., Kiesel, B.F., Chaphekar, N. et al. In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine. Cancer Chemother Pharmacol 86, 633–640 (2020). https://doi.org/10.1007/s00280-020-04154-5

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  • DOI: https://doi.org/10.1007/s00280-020-04154-5

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