Synthesis and plasma pharmacokinetics in CD-1 mice of a 18[beta]-glycyrrhetinic acid derivative displaying anti-cancer activity

• Published in: Journal of pharmacy and pharmacology Vol. 65; no. 3; p. 402
• Main Authors: Lallemand, Benjamin, Ouedraogo, Moustapha, Wauthoz, Nathalie, Lamkami, Touria, Mathieu, Veronique, Jabin, Ivan, Amighi, Karim, Kiss, Robert, Dubois, Jacques, Goole, Jonathan
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01-03-2013
• Subjects: Plasma
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/j.2042-7158.2012.01603.x

Objectives The plasma pharmacokinetic profile in CD-1 mice of a novel 18[beta]-glycyrrhetinic acid (GA) derivative, which displays invitro 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 of2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40mg/kg body weight. Key findings Compound2 displayed IC50 invitro growth inhibitory concentrations of 29 and 8μm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of 4. The intravenous pharmacokinetic parameters revealed that2 was rapidly distributed (t1/2dist of 3min) but slowly eliminated (t1/2elim=77min). 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. [PUBLICATION ABSTRACT]