The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism.

Following a single oral dose (200 mg Kg (-1) of stiripentol t (1) o adult male Sprague-Dawley rats, a total of 15 metabolites (accounting collectively for 44% of the administered dose collected over 48 hr) were identified in urine by GC/MS techniques, while only unchanged I (accounting for a further 12.8% and 23.5% of the dose in two rats) was present in extracts of feces. The major pathway of metabolism I involved cytochrome P-450-mediated cleavage of the methylenedioxy ring to yield catechol derivatives. In vitro studies employing rat hepatic microsomal preparations showed that this reaction was associated with the formation of a type III optical difference spectrum, indicative of the generation of an inhibitory ligand-complex between a reactive metabolite of I and the prosthetic heme moiety of cytochrome P-450. Mechanistic studies on the origin of a series of metabolites of I in which the allylic alcohol side chain had been replaced by an isomeric 3-pentanone structure pointed to the operation of a two-step sequence involving initial alcohol oxidation followed by olefin reduction. The former reaction appeared to be catalyzed in part by cytochrome P-450 enzymes. It is concluded that the rat represents an appropriate model for humans in the conduct of detailed studies of the metabolic fate of I and analogs thereof.

The metabolic fate of stiripentol in man.

The metabolism of stiripentol (I), a new antiepileptic drug, was studied in healthy human subjects. Following a single 1200-mg oral dose to one subject, 13 metabolites of I were detected in urine and were identified by GC/MS techniques. The structures of 9 of these metabolites were confirmed subsequently by synthesis of the corresponding reference compounds. The nature of the urinary metabolites of I revealed the operation of five distinct metabolic pathways for this drug, viz. conjugation with glucuronic acid, oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. Metabolites of I excreted into urine over 12 hr accounted for the majority (73%) of an acute dose, whereas a further 18% was recovered in feces as the unchanged drug. These findings suggested that the search for additional metabolites would yield only trace amounts. From a quantitative standpoint, the most important pathway of biotransformation of I following both acute and chronic dosing involved opening of the methylenedioxy ring to generate catechol derivatives. This finding probably accounts for the known inhibitory effects of I on the oxidative metabolism of other antiepileptic agents and for the clinically significant drug interactions involving stiripentol.

Comparison of the concentration-effect relationship of a local antiinflammatory agent and oral acetylsalicylic acid: the value of local application.

Using a pharmacological model, the comparison between acetylsalicylic acid (ASA), administered orally, and a solution combining two salicylate derivatives (ethyl 5-methoxy-salicylate and 3-phenyl-propyl-salicylate), applied locally, demonstrated the value of the local application. Indeed, the pharmacological activity was highly significant and directly related to the tissue concentration of salicyl ions, which was higher after local application of the solution than after oral administration of ASA. The local solution also resulted in a lower plasma concentration of salicylate ions, allowing high plasma salicylate concentrations to be avoided.

Bacterio-pharmacological activity of Saccharomyces boulardii in clindamycin-induced colitis in the hamster.

The effect of S. boulardii on experimental colitis induced by the single oral administration of 1 mg/kg of clindamycin in the Syrian hamster was studied. Oral administration of S. boulardii for 13 days, starting 3 days prior to the administration of clindamycin, significantly reduced the mortality rate and inhibited the growth of C. difficile in the caecum and colon. There was a marked improvement in the sub-mucosa and mucosa which showed major inflammatory lesions when clindamycin was administered alone.

[Pharmacokinetic study of 3H-stiripentol in rats (author's transl)]. / Etude pharmacocinétique du 3H-stiripentol chez le rat.

The radioactive constituents of blood, urine, and bile specimens from Wistar Rats, following intravenous administration of 3H-stiripentol were analyzed, in parallel with samples of: liver, lung, kidneys, testis, heart, brain, cerebellum, and medulla. These investigations yielded the following results: 3H-Stiripentol was quantitatively and rapidly absorbed and metabolized by Wistar rats, due to intense metabolism in the liver. The cerebellum and medulla accumulated radioactivity, which was probably related to the pharmacological effects of this drug.