Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres

Harry Cremers, H.F.M. Cremers, L.G. Bayon, R. Verrijk, M.M. Wesseling, J. Wondergem, G. Heuff, G.S. Kwon, Y.H. Bae, Jan Feijen, S.W. Kim

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Abstract

Adriamycin (ADR) was formulated in albumin-heparin conjugate microspheres (AHCMS) to improve site-specific delivery and to reduce the toxicity of the drug. The effect of formulating ADR in AHCMS was investigated upon intrahepatic administration to male Wag/Rij rats. After intraveno-portal (i.v.p.) administration of ADR-AHCMS, ADR peak plasma concentrations were reduced 10-fold and ADR tissue levels of non-target tissues were significantly reduced, as compared to i.v.p. administration of the free drug. At an i.v.p. administered drug dose of 7.5 mg/kg, free ADR showed distinct signs of acute toxicity. At the same dose of ADR-AHCMS, signs of toxicity were absent. Cardiac function parameters which were determined using an isolated working heart model did not change as a result of i.v.p. administration of free ADR or ADR-AHCMS at a dose of 7.5 mg/kg. Heart weights of animals in the ADR-AHCMS or the free ADR groups, however, were significantly lower than controls. Dose tolerance studies after intrahepatic-arterial (i.h.a.) administration of free ADR, empty AHCMS and ADR-AHCMS in rats demonstrated that empty AHCMS are tolerated at a dose of 45 mg/kg. Free ADR was tolerated at a dose of 4 mg/kg, whereas ADR-AHCMS were tolerated up to a dose of 10 mg ADR/kg, as indicated by the survival.
Original languageUndefined
Pages (from-to)51-61
JournalInternational journal of pharmaceutics
Volume120
Issue number1
DOIs
Publication statusPublished - 1995

Keywords

  • METIS-105398
  • IR-9909

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