Preclinical pharmacology of epothilone D, a novel tubulin-stabilizing antitumor agent.
OBJECTIVE
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.
Wang
Hui
H
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
Wang
Zhi
Z
Wang
Shuyi
S
Li
Mao
M
Nan
Li
L
Rhie
Julie K
JK
Covey
Joseph M
JM
Zhang
Ruiwen
R
Hill
Donald L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D034261:Epothilones / Q000097:blood / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity
D000970:Antineoplastic Agents; D034261:Epothilones; C114026:desoxyepothilone B