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Synthesis and plasma pharmacokinetics in CD-1 mice of a 18β-glycyrrhetinic acid derivative displaying anti-cancer activity.
- Source :
-
Journal of Pharmacy & Pharmacology . Mar2013, Vol. 65 Issue 3, p402-410. 9p. 1 Diagram, 2 Charts, 5 Graphs. - Publication Year :
- 2013
-
Abstract
- Objectives The plasma pharmacokinetic profile in CD-1 mice of a novel 18β-glycyrrhetinic acid ( GA) derivative, which displays in vitro anti-cancer activity, was assessed. Methods This study involved an original one-step synthesis of N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide, ( 2) a compound that displays marked anti-proteasome and anti-kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose ( MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight. Key findings Compound 2 displayed IC50 in vitro growth inhibitory concentrations of 29 and 8 μ m on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t1/2dist of ∼3 min) but slowly eliminated (t1/2elim = ∼77 min). Conclusions This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti-kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00223573
- Volume :
- 65
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmacy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 85166185
- Full Text :
- https://doi.org/10.1111/j.2042-7158.2012.01603.x