Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. I. Amrubicin accumulates to a lower level than doxorubicin or epirubicin

The Journal of Pharmacology and Experimental Therapeutics
Emanuela SalvatorelliGiorgio Minotti

Abstract

Antitumor anthracyclines such as doxorubicin and epirubicin are known to cause cardiotoxicity that correlates with anthracycline accumulation in the heart. The anthracycline amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-d-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] has not shown cardiotoxicity in laboratory animals or patients in approved or investigational settings; therefore, we conducted preclinical work to characterize whether amrubicin attained lower levels than doxorubicin or epirubicin in the heart. Anthracyclines were evaluated in ex vivo human myocardial strips incubated in plasma to which anthracycline concentrations of 3 or 10 μM were added. Four-hour incubations were performed to characterize myocardial anthracycline accumulation derived from anthracycline uptake in equilibrium with anthracycline clearance. Short-term incubations followed by multiple washouts were performed to obtain independent measurements of anthracycline uptake or clearance. In comparison with doxorubicin or epirubicin, amrubicin attained very low levels in the soluble and membrane fractions of human myocardial strips. This occurred at both 3 and 10 μM anthracycline concentrations and wa...Continue Reading

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Citations

Aug 16, 2013·Drug Design, Development and Therapy·Qian Ding, Jinbiao Zhan
Jan 18, 2015·Biochimica Et Biophysica Acta·Emanuela SalvatorelliGiorgio Minotti
Sep 24, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Marzena SzwedZofia Jozwiak
Jun 1, 2017·The Journal of Pharmacology and Experimental Therapeutics·Emanuela SalvatorelliGiorgio Minotti

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