Synthesis and plasma pharmacokinetics in CD‐1 mice of a 18β‐glycyrrhetinic acid derivative displaying anti‐cancer activity. (16th November 2012)

• Record Type: Journal Article
• Authors: Lallemand, Benjamin; Ouedraogo, Moustapha; Wauthoz, Nathalie; Lamkami, Touria; Mathieu, Veronique; Jabin, Ivan; Amighi, Karim; Kiss, Robert; Dubois, Jacques; Goole, Jonathan
• Is Part Of: Journal of pharmacy and pharmacology. Volume 65:Number 3(2013:Mar.)
• Page Start: 402
• Page End: 410
• Publication Date: 2012-11-16
• Subjects: Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.2042-7158.2012.01603.x
• Languages: English
• ISSNs: 0022-3573

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jphp1603-sec-0001" sec-type="section"> <title>Objectives</title> <p>The plasma pharmacokinetic profile in CD‐1 mice of a novel 18β‐glycyrrhetinic acid (GA) derivative, which displays <italic>in vitro</italic> anti‐cancer activity, was assessed.</p> </sec> <sec id="jphp1603-sec-0002" sec-type="section"> <title>Methods</title> <p>This study involved an original one‐step synthesis of <italic>N</italic>‐(2‐{3‐[3, 5‐bis(trifluoromethyl)phenyl]ureido}ethyl)‐glycyrrhetinamide, (<bold>2</bold>) a compound that displays marked anti‐proteasome and anti‐kinase activity. The bioselectivity profile of<bold> 2</bold> on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of<bold> 2</bold> was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight.</p> </sec> <sec id="jphp1603-sec-0003" sec-type="section"> <title>Key findings</title> <p>Compound<bold> 2</bold> displayed IC<sub>50</sub><italic>in vitro</italic> growth inhibitory concentrations of 29 and 8 μ<sc>m</sc> on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that<bold> 2</bold> was rapidly distributed (t<sub>1/2dist</sub> of ∼3 min) but slowly eliminated (t<sub>1/2elim</sub> = ∼77 min).</p> </sec> <sec id="jphp1603-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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 <italic>in vivo</italic> using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration.</p> </sec> </abstract>