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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (536)	5/4/2005 5:07:11 PM
From: tuck	Respond to of 933

[Preclinical pharmacology of Epo D: dogs better models than rodents] >>Cancer Chemother Pharmacol. 2005 May 3; [Epub ahead of print] Preclinical pharmacology of epothilone D, a novel tubulin-stabilizing antitumor agent. Wang H, Wang Z, Wang S, Li M, Nan L, Rhie JK, Covey JM, Zhang R, Hill DL. Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA, hui.wang@ccc.uab.edu. PURPOSE: To determine, for various species, the pharmacological and biochemical properties of epothilone D (EpoD) that are relevant in establishing an appropriate animal model for further evaluation of this promising antitumor agent.METHODS: A method involving high-performance liquid chromatography (HPLC) was developed and used to assess the stability and protein binding of EpoD in plasma from various species, its metabolism by various S9 fractions, and its pharmacokinetics in mice.RESULTS: EpoD was stable in dog and human plasma. In plasma from other species, stability decreased in the order: hamster > mouse > guinea pig > rat. EpoD was highly bound to proteins in dog and human plasma. In an evaluation of S9 fractions from mouse, rat, guinea pig, dog, and human, mouse S9 was most efficient in metabolizing EpoD. Following administration to CD2F1 mice, the initial half-lives for plasma elimination of EpoD were <5 min for an intravenous dose and <20 min for an intraperitoneal dose.CONCLUSIONS: The species differences in EpoD biostability and metabolism may have implications in assessing its antitumor activity and pharmacologic and toxicologic profiles in humans. Relative to humans, the mouse is not a good model for disposition of EpoD; the dog would be more appropriate.<< Cheers, Tuck