Polysaccharide pharmacokinetics: Amphotericin B arabinogalactan conjugate-A drug delivery system or a new pharmaceutical entity?

Anna Elgart; Shimon Farber; Abraham J. Domb; Itzhack Polacheck; Amnon Hoffman

doi:10.1021/bm100298r

Polysaccharide pharmacokinetics: Amphotericin B arabinogalactan conjugate-A drug delivery system or a new pharmaceutical entity?

Anna Elgart, Shimon Farber, Abraham J. Domb, Itzhack Polacheck, Amnon Hoffman^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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-M_w and L-M_w) 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-M_w and L-M_w 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.

Original language	American English
Pages (from-to)	1972-1977
Number of pages	6
Journal	Biomacromolecules
Volume	11
Issue number	8
DOIs	https://doi.org/10.1021/bm100298r
State	Published - 9 Aug 2010

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title = "Polysaccharide pharmacokinetics: Amphotericin B arabinogalactan conjugate-A drug delivery system or a new pharmaceutical entity?",

abstract = "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.",

author = "Anna Elgart and Shimon Farber and Domb, {Abraham J.} and Itzhack Polacheck and Amnon Hoffman",

year = "2010",

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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.

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Polysaccharide pharmacokinetics: Amphotericin B arabinogalactan conjugate-A drug delivery system or a new pharmaceutical entity?

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