In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine
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ORIGINAL ARTICLE
In vitro evaluation of the metabolic enzymes and drug interaction potential of triapine Anand Joshi1 · Brian F. Kiesel1,2 · Nupur Chaphekar1 · Reyna Jones2 · Jianxia Guo2 · Charles A. Kunos3 · Sarah Taylor1,4 · Edward Chu2,5 · Raman Venkataramanan1,6 · Jan H. Beumer1,2,5 Received: 4 December 2019 / Accepted: 17 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 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. Keywords Triapine · Metabolism · Drug–drug interaction · CYP450 · Metabolic pathway
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04154-5) contains supplementary material, which is available to authorized users. * Raman Venkataramanan [email protected] * Jan H. Beumer [email protected] 1
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
2
Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
3
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP, T riapine®) belongs to a class of α-Nheterocyclic thiosemicarbazones that inhibits the catalytic activity of ribonucleotide reductase (RNR) [1, 2]. RNR 4
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Pittsburgh-Magee Women’s Hospital, Pittsburgh, PA, USA
5
Division of Hematology‑Oncology, Department of Medicine, Univers
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