Small intestinal sulphoxidation of Albendazole

Villaverde, C.; Alvarez, Ana I.; Redondo, Pedro A.; Voces, J.; Estal, J.L. del; Prieto, J. E.

doi:10.3109/00498259509061863

Cited by 57 publications

(36 citation statements)

References 24 publications

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“…Inversion of the chiral sulfoxide drug flosequinan occurs in rats via reduction of the sulfoxide group to form the sulfide, followed by oxidation of the sulfide to both flosequinan enantiomers. 18,24 Sulfoxide moieties can undergo oxidative metabolism by cytochrome P450 25,26 and/or by flavin containing monooxygenase, 25,26 and can undergo reductive metabolism by aldehyde oxidase 27 and/or thioredoxin-linked enzymes. 27 Both liver and gut flora are potential sites for formation of the sulfide metabolites.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

1998

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(±)‐Pantoprazole ((±)‐PAN), (±)‐5‐(difluoromethoxy)‐2‐[[(3.4‐dimethoxy‐2‐pyridinyl)methyl]sulfinyl]‐1H‐benzimidazole is a chiral sulfoxide that is used clinically as a racemic mixture. The disposition kinetics of (+)‐PAN and (−)‐PAN given separately has been studied in rats. Serum levels of (+)‐ and (−)‐PAN and its metabolites, pantoprazole sulfone (PAN‐SO2), pantoprazole sulfide (PAN‐S), 4′‐O‐demethyl pantoprazole sulfone (DMPAN‐SO2), and 4′‐O‐demethyl pantoprazole sulfide (DMPAN‐S) were measured by HPLC. Following single intravenous or oral administration, both enantiomers were rapidly absorbed and metabolized, resulting in similar serum concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics. The major metabolite of both (+)‐ and (−)‐PAN was PAN‐SO2, while DMPAN‐SO2 was also detected as a minor metabolite. Serum levels of PAN‐S and DMPAN‐S could not be quantified after intravenous or oral administration of either enantiomer. Significant chiral inversion occurred after intravenous and oral administration of (+)‐PAN. The AUCs of (−)‐PAN after intravenous and oral dosing of (+)‐PAN were 36.3 and 28.1%, respectively of those of total [(+) + (−)] PAN. In contrast, the serum levels of (+)‐PAN were below quantitation limits after intravenous or oral administration of (−)‐PAN. Therefore, chiral inversion was observed only after administration of (+)‐PAN, supporting the hypothesis that stereoselective inversion from (+)‐PAN to (−)‐PAN occurs in rats. Chirality 10:747–753, 1998. © 1998 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

1998

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“…This metabolite is further metabolized to albendazole sulfone (ASON), which does not appear to have any activity. 17,18 Figure 2 shows the total ion chromatogram referring to the analysis of the products obtained by oxidation of ABZ with [Fe(TNPCl 8 P)]Cl porphirin after a 1 hour reaction. The products were identified by comparing their retention times with the retention times obtained by direct injection of standard solutions of ASOX (t R = 6.8 min) and ASON (t R = 5.7 min) and also using the MS scan and daughter scan spectra (Figure 3).…”

Section: Characterization and Identification Of Abz Oxidation Productsmentioning

confidence: 99%

LC-MS-MS identification of drug metabolites obtained by metalloporphyrin mediated oxidation

Maurin¹,

Iamamoto²,

Lopes³

et al. 2003

J. Braz. Chem. Soc.

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Neste artigo estamos relatando a aplicação da cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS-MS) para a identificação dos produtos formados na oxidação de albendazol e disopiramida utilizando metaloporfirinas em dicloroetano como catalisador e iodozilbenzeno como doador de oxigênio. Nossos resultados comprovam que LC-MS-MS é uma poderosa técnica para o estudo in vitro de metabolismo de fármacos, permitindo a identificação de metabólitos conhecidos ou não. Foi observado que o sistema catalítico usado resultou na formação dos mesmos metabólitos obtidos in vivo, embora outros produtos também foram formados na oxidação da disopiramida.In this paper we report the application of liquid chromatography-mass spectrometry (LC-MS-MS) to the identification of the products formed by oxidation of albendazole and disopyramide with metalloporphyrins in dichloroethane, using iodosylbenzene as an oxygen donor. Our results show that LC-MS-MS is a powerful tool to study the in vitro metabolism of drugs, allowing the identification of known and unknown metabolites. In addition, it was observed that the catalyst system used resulted in the formation of the same metabolites as obtained in vivo, although for disopyramide other products were also observed.

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“…Furthermore, benzimidazoles undergo extensive intestinal and hepatic bioconversion, adding to the low systemic exposures with these compounds [5,6]. In case of albendazole, different cytochrome P450 enzymes (CYP) and the flavine-containing monooxygenase (FMO) system seem to be responsible for intestinal and hepatic sulfoxidation of the parent compound to albendazole sulfoxide [6,7], while CYP1A2 is involved in sulfonidation [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Corti

Heck

Rentsch

et al. 2009

Eur J Clin Pharmacol

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Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers Abstract BACKGROUND: Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir. METHODS: Sixteen healthy volunteers were administered a single oral dose of 1,000 mg mebendazole or 400 mg albendazole (2 x n = 8). AUC, C(max), and t(1/2) of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg bid. RESULTS: Pharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC(0-24) (27 and 43% of baseline for albendazole and mebendazole, respectively) and C(max) (26 and 41% of baseline, respectively). CONCLUSION: The AUC(0-24) of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitors.

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Small intestinal sulphoxidation of Albendazole

Cited by 57 publications

References 24 publications

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats

LC-MS-MS identification of drug metabolites obtained by metalloporphyrin mediated oxidation

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

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