TY - JOUR
T1 - Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres
AU - Cremers, Harry
AU - Cremers, H.F.M.
AU - Bayon, L.G.
AU - Verrijk, R.
AU - Wesseling, M.M.
AU - Wondergem, J.
AU - Heuff, G.
AU - Kwon, G.S.
AU - Bae, Y.H.
AU - Feijen, Jan
AU - Kim, S.W.
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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.
KW - METIS-105398
KW - IR-9909
U2 - 10.1016/0378-5173(94)00408-W
DO - 10.1016/0378-5173(94)00408-W
M3 - Article
SN - 0378-5173
VL - 120
SP - 51
EP - 61
JO - International journal of pharmaceutics
JF - International journal of pharmaceutics
IS - 1
ER -