title: Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function.
abstract: BACKGROUND
  Sunitinib, a multi-tyrosine kinase inhibitor has demonstrated clinical activity in advanced renal cell carcinoma and imatinib-resistant/intolerant gastrointestinal stromal tumor. It has been associated with manageable hypertension and other unique toxicities.
  
  
  OBJECTIVE
  Two nonclinical studies were conducted to determine if sunitinib has direct/indirect effects on cardiac structure/function that may be related to hypertension at clinically relevant exposures.
  
  
  METHODS
  Rats received once-daily vehicle or sunitinib 1 or 10 mg/kg/day (n = 10/group) orally for 4 weeks, followed by 2 weeks off treatment then a 2-week rechallenge. Blood pressure (BP) and heart rate (HR) were continuously acquired and echocardiograms were obtained weekly. Effects of sunitinib and its metabolite (0.003-0.3 μM) were also evaluated in guinea pig isolated Langendorff-perfused hearts (n = 4-6 hearts/group).
  
  
  RESULTS
  Sunitinib 10 mg/kg/day produced significant (P < 0.05) hemodynamic changes: 24 h average BP increased during initial dosing/rechallenge, with rebound hypotension during the off-treatment period; 24 h average HR increased during the off-treatment period, and decreased during rechallenge; no changes in cardiac structure/function were observed. In guinea pig isolated hearts, neither sunitinib nor its metabolite had direct effects on contractility, HR or left ventricular pressure.
  
  
  CONCLUSIONS
  These studies demonstrate that sunitinib/metabolite had no direct effects on cardiac function ex vivo, and that therapeutically relevant concentrations of sunitinib dosed on a "clinical schedule" increased BP in rats without adverse changes in cardiac structure/function.
authors: Safety Pharmacology-Pfizer Global Research and Development, La Jolla, CA, USA. eileen.r.blasi@pfizer.com
authors: E
authors: E
authors: Blasi
authors: J
authors: J
authors: Heyen
authors: S
authors: S
authors: Patyna
authors: M
authors: M
authors: Hemkens
authors: D
authors: D
authors: Ramirez
authors: A
authors: A
authors: John-Baptiste
authors: J
authors: J
authors: Steidl-Nichols
authors: A
authors: A
authors: McHarg
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects*; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006168:Guinea Pigs; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077210:Sunitinib; D013686:Telemetry
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib