Synthesis and plasma pharmacokinetics in CD-1 mice of a 18β-glycyrrhetinic acid derivative displaying anti-cancer activity.
OBJECTIVE
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.


RESULTS
Compound 2 displayed IC(50)  in vitro growth inhibitory concentrations of 29 and 8 μm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t(1/2dist)  of ∼3 min) but slowly eliminated (t(1/2elim)  = ∼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.
Laboratory of Bioanalytical Chemistry, Toxicology, and Applied Chemistry, Université de Ouagadougou(U.L.B), Brussels, Belgium. benjamin.lallemand@ulb.ac.be
Benjamin
B
Lallemand
Moustapha
M
Ouedraogo
Nathalie
N
Wauthoz
Touria
T
Lamkami
Veronique
V
Mathieu
Ivan
I
Jabin
Karim
K
Amighi
Robert
R
Kiss
Jacques
J
Dubois
Jonathan
J
Goole
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004655:Emulsions / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010316:Particle Size; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D004655:Emulsions; C119129:18alpha-glycyrrhetinic acid; D046988:Proteasome Endopeptidase Complex; D006034:Glycyrrhetinic Acid