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Pharmacodynamic and pharmacokinetic characteristics of YMR-65, a tubulin inhibitor, in tumor-bearing mice.
- Source :
-
European Journal of Pharmaceutical Sciences . Aug2018, Vol. 121, p74-84. 11p. - Publication Year :
- 2018
-
Abstract
- YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t 1/2 ) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC 0–∞ ) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUC tissue or tumor /AUC plasma ) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PHARMACODYNAMICS
*PHARMACOKINETICS
*TUBULINS
*APOPTOSIS
Subjects
Details
- Language :
- English
- ISSN :
- 09280987
- Volume :
- 121
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 130419373
- Full Text :
- https://doi.org/10.1016/j.ejps.2018.05.011