Distribution, metabolism, and excretion of toceranib phosphate (Palladia SU11654), a novel tyrosine kinase inhibitor, in dogs

• Published in: Journal of veterinary pharmacology and therapeutics Vol. 33; no. 2; pp. 154 - 161
• Main Authors: YANCEY, M.F, MERRITT, D.A, WHITE, J.A, MARSH, S.A, LOCUSON, C.W
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-04-2010; Blackwell Publishing Ltd
• Subjects: absorption; Animals; antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; biochemical pathways; blood plasma; dogs; Dogs - metabolism; drug evaluation; drug excretion; enzyme inhibitors; excreta; Female; half life; Hepatocytes - metabolism; in vitro studies; in vivo studies; Indoles - blood; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacokinetics; liver; liver function; Male; Microsomes - metabolism; Molecular Structure; new drugs; oral administration; pharmacokinetics; Plasma; Protein Binding; protein-tyrosine kinases; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrroles - blood; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacokinetics; radiolabeling; Tissue Distribution; toceranib; toceranib phosphate; uptake mechanisms; veterinary drugs
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/j.1365-2885.2009.01120.x

Toceranib phosphate (Palladia[trade mark sign], SU11654), a multireceptor tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, has been developed for the treatment of mast cell tumors in dogs. An overview of the distribution, metabolism, and excretion of toceranib phosphate in dogs is presented. When [¹⁴C]-toceranib was orally administered to dogs, the majority of the radioactivity (92%) was excreted in feces and only a small portion (7%) was excreted in urine. Seven days after a single 3.25 mg/kg oral dose, radioactivity was the highest in bile and liver, with measurable concentrations in lymph nodes, colon, adrenals, bone marrow, kidneys, lungs, spleen, pancreas, and skin. Plasma protein binding of toceranib in fresh plasma ranged from 90.8% to 92.8% at concentrations between 20 ng/mL and 500 ng/mL and was independent of concentration. Microsomal and hepatocyte incubations resulted in the formation of a single metabolite. Spectrometric analysis of the metabolite was consistent with the formation of an alicyclic N-oxide of toceranib. The combination of the high rate of fecal excretion and the long elimination half-life of toceranib indicate enterohepatic recirculation of the parent compound and/or the N-oxide metabolite.