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The Contribution of Pets to Human and Veterinary Medicine
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Toceranib (SU11654) is a receptor tyrosine kinase (RTK) inhibitor that is used to treat canine mast cell tumors. Toceranib phosphate was approved by the FDA for animal use in 2009, under the tradename Palladia™ (Zoetis, Parsippany, NJ). Sunitinib (SU11248) is a receptor tyrosine kinase inhibitor closely related to SU11654 that is used to treat renal cell carcinoma in people as well as specific types of gastrointestinal cancer. Sunitinib was approved by the FDA in 2006 as Sutent®. These two molecules are structural cousins. Pharmaceutical company Sugen conducted the original research on both of these molecules and became interested in targeting KIT receptor tyrosine kinases found in certain human cancers (gastrointestinal stromal tumors, small lung cancers, acute myeloid leukemia) during the late 1990s. At that time, the company became aware of the role of KIT mutations in canine mast cell tumors (a common cancer type found in dogs). A small clinical trial was performed in canine patients with mast cell tumors and results were promising, thereby providing useful proof of concept data to encourage translational research in humans. Furthermore, SU11654 demonstrated pharmacokinetic (PK) properties comparable to SU11248 in dogs. In fact, Sutent does not have a high therapeutic index and the PK properties seen in dogs are much better approximations of human PK properties than that seen in murine models. The fact that some of the same mutations identified in human gastrointestinal stroma tumors were present in canine mast cell tumors made this research especially informative.
Comparison of predicted intrinsic hepatic clearance of 30 pharmaceuticals in canine and feline liver microsomes
Published in Xenobiotica, 2019
Marike Visser, Matthew J. Zaya, Charles W. Locuson, Dawn M. Boothe, Dawn A. Merritt
Selected substrates were chosen based on reported CYP activity in humans or canines, compounds within the same drug class (e.g. benzodiazepines), or reported to have significantly different in vivo clearance between canine and feline. Alprazolam, amitriptyline, carvedilol, clarithromycin, clomipramine, cyclosporin, desipramine, diazepam, enrofloxacin, fluvoxamine, loperamide, maropitant, metoclopramide, midazolam, mirtazapine, omeprazole, ondansetron, phenacetin, pimobendan, praziquantel, quinidine, testosterone, toceranib and vincristine were purchased from Sigma-Aldrich (St. Louis, MO). Additional substrates purchased were grapiprant (MedChemExpress, Princeton, NJ), cyclophosphamide (MP Biomedicals, Solon, OH), vincristine and metronidazole (Alfa Aesar, Ward Hill, MA) and fluoxetine (Toronto Research Chemicals Inc., North York, ON, Canada).