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

Cancer Chemother Pharmacol. 2020 Nov;86(5):633-640. doi: 10.1007/s00280-020-04154-5. Epub 2020 Sep 28.

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: CYP450; Drug–drug interaction; Metabolic pathway; Metabolism; Triapine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Chemoradiotherapy / methods
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors / pharmacokinetics*
  • Cytochrome P-450 CYP1A2 Inhibitors / therapeutic use
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 CYP2C19 Inducers / pharmacokinetics*
  • Cytochrome P-450 CYP2C19 Inducers / therapeutic use
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Emtricitabine / pharmacokinetics
  • Hepatocytes
  • Humans
  • Inactivation, Metabolic
  • Microsomes, Liver
  • Neoplasms / therapy*
  • Primary Cell Culture
  • Pyridines / pharmacokinetics*
  • Pyridines / therapeutic use
  • Radiation-Sensitizing Agents / pharmacokinetics*
  • Radiation-Sensitizing Agents / therapeutic use
  • Tandem Mass Spectrometry
  • Tenofovir / pharmacokinetics
  • Thiosemicarbazones / pharmacokinetics*
  • Thiosemicarbazones / therapeutic use

Substances

  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2C19 Inducers
  • Pyridines
  • Radiation-Sensitizing Agents
  • Thiosemicarbazones
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • Tenofovir
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Emtricitabine