Tissue distribution of crizotinib and gemcitabine combination in a patient-derived orthotopic mouse model of pancreatic cancer

  • Richard J. Honeywell Department of Medical Oncology, VU University Medical Center PO Box 7057 1007 MB Amsterdam The Netherlands
  • Amir Avan Molecular Medicine Group, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Elisa Giovannetti Department of Medical Oncology, VU University Medical Center PO Box 7057 1007 MB Amsterdam The Netherlands
  • Godefridus J. Peters VU University Medical Center
Keywords: Crizotinib, gemcitabine, tissue distribution

Abstract

Pharmacokinetics focuses on the question whether a drug actually reaches its target in therapeutic concentrations or accumulates elsewhere, potentially causing toxicological or unpredictable side effects. We determined tissue distribution of gemcitabine, an antimetabolite, and crizotinib, a tyrosine-kinase inhibitor targeted against the anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met) receptors, in a validated orthotopic mouse model for pancreatic cancer. Mice with pancreatic cancer were treated with either oral crizotinib at 25 mg/kg, gemcitabine at 100 mg/kg or with their combination. Two hours after the last gemcitabine dose mice were sacrificed and all available blood/organs/tissues were sampled. Tissue was subsequently analyzed for drug concentrations using a validated liquid chromatography-mass spectrometry (LC-MS/MS) technique. In whole blood gemcitabine was about 1.0 µM and crizotinib 2.4 µM in the single treatment, whereas in the combination crizotinib increased the levels of gemcitabine. Crizotinib was found in all major tissues, being highest in the intestine. Comparison of crizotinib alone to the gemcitabine-crizotinib combination showed that crizotinib tissue concentrations were 3-6 fold lower in liver, lung, kidney and spleen, 30-fold lower in the skin, heart and pancreas and 200-fold lower in the brain. Tissue gemcitabine was highest in spleen and skin, being about 5-10 fold higher than in the other tissues, including brain, which still had a relatively high accumulation. In conclusion, both gemcitabine and crizotinib accumulate at clinically active but variable levels in tissues, possibly relating to the effects exerted by these drugs.

Downloads

Download data is not yet available.
Published
26-12-2016
Section
Original Scientific Articles