Anand Joshi1, Brian F Kiesel1,2, Nupur Chaphekar1, Reyna Jones2, Jianxia Guo2, Charles A Kunos3, Sarah Taylor1,4, Edward Chu2,5, Raman Venkataramanan6,7, Jan H Beumer8,9,10. 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. 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, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 6. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA. rv@pitt.edu. 7. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA. rv@pitt.edu. 8. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA. beumerj@gmail.com. 9. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. beumerj@gmail.com. 10. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beumerj@gmail.com.
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.
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 cancerpatients 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.
Authors: Siamak Cyrus Khojasteh; Saileta Prabhu; Jane R Kenny; Jason S Halladay; Anthony Y H Lu Journal: Eur J Drug Metab Pharmacokinet Date: 2011-02-19 Impact factor: 2.441
Authors: John Murren; Manuel Modiano; Caroline Clairmont; Paula Lambert; Niramol Savaraj; Terry Doyle; Mario Sznol Journal: Clin Cancer Res Date: 2003-09-15 Impact factor: 12.531
Authors: Joshua F Zeidner; Judith E Karp; Amanda L Blackford; B Douglas Smith; Ivana Gojo; Steven D Gore; Mark J Levis; Hetty E Carraway; Jacqueline M Greer; S Percy Ivy; Keith W Pratz; Michael A McDevitt Journal: Haematologica Date: 2013-12-20 Impact factor: 9.941
Authors: Jennifer J Knox; Sebastien J Hotte; Christian Kollmannsberger; Eric Winquist; Bryn Fisher; Elizabeth A Eisenhauer Journal: Invest New Drugs Date: 2007-03-28 Impact factor: 3.850
Authors: C M Nutting; C M L van Herpen; A B Miah; S A Bhide; J-P Machiels; J Buter; C Kelly; D de Raucourt; K J Harrington Journal: Ann Oncol Date: 2009-02-26 Impact factor: 32.976