title: Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice.
abstract: Lipophilic-hydrophilic balance is a quite important determinant of pharmacokinetic properties of pharmaceuticals. Thus it is a key step to successfully manage lipophilic-hydrophilic balance in drug design. We have designed unique modular molecules, symmetrically branched oligoglycerols  (BGL) as an alternative means to endow hydrophobic molecules with much hydrophilicity. We have succeeded in improving the water-solubility of several hydrophobic medicinal small molecules and thermal stability of artificial protein by covalent conjugation to BGL. We have also demonstrated that a representative BGL, symmetrically branched glycerol trimer (BGL003) does not exhibit significant cytotoxicity against human hepatocarcinoma HepG2 cells. However, there have been no reports suggesting whether BGL could be used in safety in vivo. Therefore, evaluation of acute oral toxicity of BGL003 in healthy mice was conducted. Here we demonstrate that an oral administration of BGL003 did not exhibit acute lethal toxicity up to 3,000 mg/kg. Body weight, food intake, blood glucose levels and weights of tissues were not affected by a short-term repetitive administration of increasing doses of BGL003. Biochemical indications related to hepatic disorders and tissue damage were unchanged, either. A single administration study revealed that 50% lethal dose of BGL003 should be more than 2,000 mg/kg. BGL003 will be safe and suitable approach to improve hydrophilicity of hydrophobic compounds.
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. licht_corresp2011@yahoo.co.jp
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tomida
authors.forename: Mai
authors.initials: M
authors.lastname: Kono
authors.forename: Shoko
authors.initials: S
authors.lastname: Fujii
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Hatsuhiko
authors.initials: H
authors.lastname: Hattori
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Hisao
authors.initials: H
authors.lastname: Nemoto
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015195:Drug Design; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008968:Molecular Conformation; D011108:Polymers; D012995:Solubility
chemical_list: D011108:Polymers; D005990:Glycerol