Wang Hui, Wang Zhi, Wang Shuyi, Li Mao, Nan Li, Rhie Julie K, Covey Joseph M, Zhang Ruiwen, Hill Donald L
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cancer Chemother Pharmacol. 2005 Sep;56(3):255-60. doi: 10.1007/s00280-004-0965-0. Epub 2005 May 3.
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.
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.
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.
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.
针对不同物种，确定埃坡霉素D（EpoD）的药理学和生化特性，这些特性对于建立合适的动物模型以进一步评估这种有前景的抗肿瘤药物具有重要意义。
开发了一种涉及高效液相色谱（HPLC）的方法，并用于评估EpoD在不同物种血浆中的稳定性和蛋白结合情况、其在各种S9组分中的代谢情况以及在小鼠体内的药代动力学。
EpoD在犬和人血浆中稳定。在其他物种的血浆中，稳定性按以下顺序降低：仓鼠>小鼠>豚鼠>大鼠。EpoD与犬和人血浆中的蛋白质高度结合。在对小鼠、大鼠、豚鼠、犬和人的S9组分进行评估时，小鼠S9在代谢EpoD方面效率最高。给CD2F1小鼠给药后，静脉注射剂量的EpoD血浆消除初始半衰期<5分钟，腹腔注射剂量的<20分钟。
EpoD生物稳定性和代谢的物种差异可能对评估其在人体内的抗肿瘤活性、药理学和毒理学特征具有影响。相对于人类，小鼠不是用于EpoD处置的良好模型；犬会更合适。
