title: Cardiovascular differentiation of imatinib and bosutinib in the rat.
abstract: Imatinib and bosutinib were administered to rats for up to 6 months at clinically relevant exposures to investigate the effects on the cardiovascular system. Imatinib treatment resulted in increased volume, wall thickness and mass suggesting a hypertrophic heart in male and female rats at one and fivefold clinical exposures, respectively. Bosutinib treatment resulted in milder cardiac hypertrophy in female rats only at fivefold clinical exposures. Analysis of excised hearts and cultured myocytes demonstrated increased expression of hypertrophic genes with imatinib or analogs, but not bosutinib or c-Abl RNAi treatment. The current dataset suggests that cardiovascular liability of imatinib and bosutinib are differentiated preclinically and c-Abl independent.
authors.affiliation: Drug Safety Research and Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA, 92121, USA, jonathan.r.heyen@pfizer.com.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Heyen
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.forename: Joseph
authors.initials: J
authors.lastname: Jamieson
authors.forename: Stephane
authors.initials: S
authors.lastname: Thibault
authors.forename: Minerva
authors.initials: M
authors.lastname: Batugo
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Loi
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Burns-Naas
authors.forename: Aileen D
authors.initials: AD
authors.lastname: McHarg
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D002312:Cardiomyopathy, Hypertrophic / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology; D004452:Echocardiography; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D000068877:Imatinib Mesylate; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D009929:Organ Size; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D051381:Rats; D012737:Sex Factors
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl