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-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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, and Department of Clinical Microbiology and Infectious Diseases, The Hebrew University of Jerusalem-Hadassah Medical Center, P.O. Box 12065, Jerusalem 91120, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Elgart
authors.forename: Shimon
authors.initials: S
authors.lastname: Farber
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.forename: Itzhack
authors.initials: I
authors.lastname: Polacheck
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000666:Amphotericin B / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005685:Galactans / Q000737:chemistry*; D006207:Half-Life; D008297:Male; D011134:Polysaccharides / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D005685:Galactans; D011134:Polysaccharides; D000666:Amphotericin B; C005653:arabinogalactan