TY - JOUR
T1 - Polysaccharide pharmacokinetics
T2 - Amphotericin B arabinogalactan conjugate-A drug delivery system or a new pharmaceutical entity?
AU - Elgart, Anna
AU - Farber, Shimon
AU - Domb, Abraham J.
AU - Polacheck, Itzhack
AU - Hoffman, Amnon
PY - 2010/8/9
Y1 - 2010/8/9
N2 - Conjugation of poorly soluble drugs to polysaccharides affects their solubility, pharmacokinetics (PK), and pharmacodynamics. The need for amphotericin B (AmB) analog with improved solubility and reduced toxicity is immense. Conjugation of AmB to arabinogalactan (AG) produced a highly soluble AmB-AG conjugate, with high and low molecular weight (H-Mw and L-Mw) fractions. Its similar antifungal activity to AmB poses the question whether AmB-AG is a prodrug of AmB or a novel pharmaceutical entity. We compared the PK of AmB-AG and AmB in rats. Upon AmB-AG administration, no free AmB was released. The half-lives and the volumes of distribution of AmB, H-Mw and L-Mw were 10.9, 8.8, and 1.5 h and 1630, 217, and 133 mL/kg, respectively. We conclude that PK of small molecules conjugated to polysaccharides is mainly dictated by the macromolecular moiety and shows molecular weight dependency. Our findings define AmB-AG as a novel pharmaceutical entity with high clinical potential.
AB - Conjugation of poorly soluble drugs to polysaccharides affects their solubility, pharmacokinetics (PK), and pharmacodynamics. The need for amphotericin B (AmB) analog with improved solubility and reduced toxicity is immense. Conjugation of AmB to arabinogalactan (AG) produced a highly soluble AmB-AG conjugate, with high and low molecular weight (H-Mw and L-Mw) fractions. Its similar antifungal activity to AmB poses the question whether AmB-AG is a prodrug of AmB or a novel pharmaceutical entity. We compared the PK of AmB-AG and AmB in rats. Upon AmB-AG administration, no free AmB was released. The half-lives and the volumes of distribution of AmB, H-Mw and L-Mw were 10.9, 8.8, and 1.5 h and 1630, 217, and 133 mL/kg, respectively. We conclude that PK of small molecules conjugated to polysaccharides is mainly dictated by the macromolecular moiety and shows molecular weight dependency. Our findings define AmB-AG as a novel pharmaceutical entity with high clinical potential.
UR - http://www.scopus.com/inward/record.url?scp=77955563140&partnerID=8YFLogxK
U2 - 10.1021/bm100298r
DO - 10.1021/bm100298r
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C2 - 20690709
AN - SCOPUS:77955563140
SN - 1525-7797
VL - 11
SP - 1972
EP - 1977
JO - Biomacromolecules
JF - Biomacromolecules
IS - 8
ER -