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


Cremers, H.F.M. and Bayon, L.G. and Verrijk, R. and Wesseling, M.M. and Wondergem, J. and Heuff, G. and Kwon, G.S. and Bae, Y.H. and Feijen, J. and Kim, S.W. (1995) Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres. International journal of pharmaceutics, 120 (1). pp. 51-61. ISSN 0378-5173

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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.
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Copyright:© 1995 Elsevier
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