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Cardiovascular differentiation of imatinib and bosutinib in the rat

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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.

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Acknowledgments

The authors would like to recognize and thank Penny Venne, Michelle Hemkens, Kimbie Palacio, Penny Khamphavong, Perrine Hoerter and Tae Sung for their valuable scientific and technical contributions to the current studies. The authors would also like to thank Paul Butler, Mark Shapiro, Nathalie Bouxin and Martin Finkelstein for their critical review of the current manuscript.

Conflict of interest

All authors were employees of Pfizer, Inc. during the completion of the work.

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Authors and Affiliations

  1. Drug Safety Research and Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA, 92121, USA

    Jonathan R. Heyen, Wenyue Hu, Joseph Jamieson, Stephane Thibault, Leigh Ann Burns-Naas, Aileen D. McHarg & Bart Jessen

  2. Pfizer La Jolla, Pharmacokinetics, Dynamics and Metabolism, La Jolla Laboratories, San Diego, CA, USA

    Minerva Batugo & Cho-Ming Loi

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  1. Jonathan R. Heyen
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  2. Wenyue Hu
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Correspondence to Jonathan R. Heyen.

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Heyen, J.R., Hu, W., Jamieson, J. et al. Cardiovascular differentiation of imatinib and bosutinib in the rat. Int J Hematol 98, 597–607 (2013). https://doi.org/10.1007/s12185-013-1453-2

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  • DOI: https://doi.org/10.1007/s12185-013-1453-2

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