Paul Delatour

(−)-R-fenoprofen: Formation of fenoprofenyl-coenzyme A by rat liver microsomes

The thioesterification of fenoprofen (FPF) by rat liver microsomes has been studied using an HPLC method enabling direct quantification of the FPF-CoA produced. Over the concentration range studied (5-400 microM), studies showed the participation of a single CoA ligase in the formation of FPF-CoA, in contrast with the involvement of several isozymes with different affinities, that has been found with ibuprofen (IPF). The Km for the reaction was dependent upon the presence of non-ionic detergent, a concentration of 0.05% Triton X-100 reducing the Km from 397 to 20 microM although the detergent had no effect on Vmax. The microsomal long-chain fatty acid CoA ligase was markedly enantioselective towards (-)-R-FPF and the formation of (-)-R-FP-CoA was inhibited by both the (+)-S enantiomer and palmitic acid.

Stereoselective S-oxygenation of an aryl-trifluoromethyl sulfoxide to the corresponding sulfone by rat liver cytochromes P450

Toltrazuril sulfoxide (TZR.SO) is the metabolite of the antiparasitic drug toltrazuril (TZR; 1-methyl-3-[3-methyl-4-[4-[trifluoromethyl]thio]phenoxy]phenyl- 1,3,5-triazine-2,4,6(1H,3H,5H)-trione). The results of the present paper demonstrate that TZR.SO was metabolized by rat liver microsomes to the corresponding sulfone (TZR.SO2). The reaction was mediated almost exclusively by different cytochromes P450, the most active being cytochromes P450 3A. TZR.SO exists as a racemic mixture; when each enantiomer was incubated separately in the presence of untreated rat liver microsomes, a 7.3-fold difference in the rate of S-oxygenation was found, indicating a marked substrate enantioselectivity for the reaction.

Anthelmintic activity of 3,6-dibenzyl-2,5-dioxopiperazine, cyclo(L-Phe-L-Phe)

SummaryAfter oral administration, dipeptide Phe-Phe-OMe1 exhibits anthelmintic activity againstEchinococcus multilocularis larvae, cestoda, in mongolian gerbils (intraperitoneal localization), but not againstHymenolepis nana, cestoda, in fasted mice (gastro-intestinal localization). This compound rapidly provides its cyclization product dioxopiperazine2 in pH 7.4 buffer at 37°C, but was stable at pH 2.4 during 16h at 30°C. It was postulated that dipeptide1 could act as a prodrug of2. Initial pharmacokinetics studies were carried out in mice and dogs. After oral administration, biotransformation of1 into2 occurred to some extent in mice but not in fasted dogs. Results of these studies did not allow to ascertain that1 is a prodrug of2. Compound2 has been tested in mice againstH. nana andSchistosoma mansoni, a gastrointestinal trematoda. Albeit less active than the reference compound praziquantel,2 has shown a good activity against both worms. 2,5dioxopiperazines represent therefore a new class of anthelmintics.

Pharmacokinetics of an anthelmintic potential prodrug of a new benzimidazole in gerbil, mouse and sheep

Abstract N -Methoxycarbonyl- N ′-2-nitro-4-trifluoromethyl phenyl thiourea ( 1 ) possesses a good activity against Echinoccus multilocularis metacestodes in gerbil. This compound has been synthesized as a potential prodrug of benzimidazole carbamate ( 2 ). Compound 2 is less active against the parasite. The pharmacokinetics of 1 and 2 have been investigated in sheep, gerbil and mouse. The results indicate that 1 is actually metabolized into 2 . Its metabolization is not complete in rodents. Plasma levels of 2 after its oral administration to gerbils are theoretically high enough for therapeutic action of a benzimidazole compound, but thiourea 1 could also possess a specific activity.