title: A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition.
abstract: PF-04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off-target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF-04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague-Dawley rat hearts in a 6 day repeat dose study with PF-04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c-AMP) pathway. PDE inhibition and activation of c-AMP were further substantiated using PDE3B immunofluorescence staining and through a c-AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF-04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose-dependent increase in intracellular calcium with PF-04254644 treatment. These data suggest that cardiotoxicity of PF-04254644 was probably due to activation of c-AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF-04254644 as compared with milrinone in gene expression and micro- and ultrastructural changes is probably due to the broader panel of PDEs inhibition.
authors.affiliation: Pfizer Inc, Drug Safety Research and Development, La Jolla Laboratories, 10646 Science Center Drive, San Diego, CA 92121, USA. Wenyue.Hu@Pfizer.com
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.forename: Brad
authors.initials: B
authors.lastname: Hirakawa
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
authors.forename: Michelle
authors.initials: M
authors.lastname: Lee
authors.forename: Shirley
authors.initials: S
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011804:Quinolines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C551178:PF-04254644; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D000242:Cyclic AMP; D020105:Milrinone; D002118:Calcium