Preclinical pharmacology of epothilone D, a novel tubulin-stabilizing antitumor agent

• Published in: Cancer chemotherapy and pharmacology 2005-09, Vol.56 (3), p.255-260
• Main Authors: HUI WANG, ZHI WANG, SHUYI WANG, MAO LI, LI NAN, RHIE, Julie K, COVEY, Joseph M, RUIWEN ZHANG, HILL, Donald L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Dogs; Drug Evaluation, Preclinical; Drug Stability; Epothilones - blood; Epothilones - pharmacokinetics; Guinea Pigs; Humans; Male; Medical sciences; Mice; Mice, Inbred Strains; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Protein Binding; Rats; Species Specificity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-004-0965-0

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