Le syndrome de l’intestin irritable : toujours d’actualité

Mion, François; Ducrotté, Philippe

doi:10.1016/s0399-8320(09)71518-0

Gastroentérologie Clinique et Biologique

2009

DOI: 10.1016/s0399-8320(09)71518-0

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Le syndrome de l’intestin irritable : toujours d’actualité

François Mion

Philippe Ducrotté

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Cited by 2 publications

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“…1) is a nootropic compound (smart drug) that acts as a mild stimulant, affecting dopamine levels in the brain, and is said to improve short‐term memory, learning and cognition 1–6. It has been withdrawn from the market due to adverse side effects, including liver toxicity7, 8 and severe fever 9. There is a possibility that reactive metabolites are involved in the toxicity of fipexide, although no conclusive experimental data have ever been shown to prove this hypothesis.…”

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Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Sleno

Staack

Varesio

et al. 2007

Rapid Comm Mass Spectrometry

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The in vitro metabolism of the nootropic drug fipexide was studied using different liquid chromatography/mass spectrometry (LC/MS) techniques. This drug has been withdrawn from the market due to toxic effects. No previous reports have investigated the possible involvement of reactive metabolites in the toxicity of fipexide. The hydrolysis of this drug leads to the formation of two potentially toxic species, 3,4-methylenedioxybenzylpiperazine (MDBP) and 4-chlorophenoxyacetic acid (4-CPA). Here, we investigate the in vitro metabolism of fipexide in human, rat, mouse and dog, as well as of MDBP and 4-CPA in human and rat, while focusing on the formation of reactive metabolites. A combination of LC/MS analyses on a hybrid quadrupole-linear ion trap instrument and accurate mass data from QqTOF measurements was employed for the characterization of these metabolites. Microsomal metabolites of fipexide were MDBP, 4-CPA, fipexide N-oxide or hydroxyl, demethylenated fipexide and other minor ones, all of which were investigated by tandem mass spectrometry. Reactive metabolites were detected using several trapping procedures with small molecules such as glutathione, its ethyl ester derivative and N-acetylcysteine. The demethylenated metabolite, a catechol, formed its corresponding ortho-quinone, which readily reacts with these nucleophiles. MDBP was studied in a similar manner, due to its ability to form an analogous catechol. Because of its acidic nature, 4-CPA was assessed for possible acylglucuronide and acyl-CoA thioester metabolites, which could also be involved in bioactivation pathways. Several important metabolites were identified as potential mediators of toxicity via protein binding.

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mentioning

confidence: 99%

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Sleno

Staack

Varesio

et al. 2007

Rapid Comm Mass Spectrometry

View full text Add to dashboard Cite

show abstract

“…Fipexide (Vigilor®, 1‐[2‐(4‐chlorophenoxy)acetyl]‐4‐(3,4‐methylenedioxybenzyl)piperazine), a nootropic drug, acts as a mild stimulant, affecting brain dopamine levels 1–6. It has been shown to increase short‐term memory, learning and cognition; however, it has been withdrawn from the market due to serious toxic effects 7–9. An important catechol metabolite, demethylenated fipexide, has been found to form glutathione (GSH) and N ‐acetylcysteine (NAC) adducts in in vitro microsomal incubations 10.…”

mentioning

confidence: 99%

Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactive metabolite in covalent binding

Sleno

Varesio

Hopfgartner

2007

Rapid Comm Mass Spectrometry

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Fipexide is a nootropic drug, withdrawn from the market due to its idiosyncratic drug reactions causing adverse effects in man. Previous work on its metabolites has identified several potential reactive metabolites which could be implicated in protein binding. Here, we investigated the formation of these metabolites in rat and human hepatocytes. Based on these results, the o-quinone of fipexide (FIP), formed via the demethylenation reaction through a catechol intermediate, was chosen for further investigation. Studies were then pursued in order to relate this metabolite to protein binding, and thus better understand potential mechanisms for the toxicity of the parent compound. An assay was developed for determining the fipexide catechol-cysteine adduct in the microsomal protein fractions following in vitro incubations. This method digests the entire protein fraction into amino acids, followed by the detection of the Cys-metabolite adduct by liquid chromatography/mass spectrometry (LC/MS). We have designed a strategy where drug metabolism taking place in microsomal incubations and involved in protein binding can be assessed after the proteins have been digested, with the detection of the specific amino acid adduct. In this study, the structure of the fipexide adduct was hypothesized using knowledge previously gained in glutathione and N-acetylcysteine trapping experiments. Acetaminophen was used as a positive control for detecting a drug metabolite-cysteine adduct by LC/MS. This approach has the potential to be applicable as a protein-binding assay in early drug discovery without the need for radioactive compounds.

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Le syndrome de l’intestin irritable : toujours d’actualité

Cited by 2 publications

References 11 publications

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactive metabolite in covalent binding

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