Investigation of the metabolites of tofizopam in man and animals by gas-liquid chromatography-mass spectrometry

Tomori, É.; Horváth, Gy.; Elekes, I.; Láng, Tibor; Kőrösi, Jenő

doi:10.1016/s0021-9673(00)82392-4

Cited by 10 publications

(4 citation statements)

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“…Animal models on both (R)-and (S)-tofisopam suggest that they decrease visceral hypersensitivity, have no effect on normal gastrointestinal function, and normalize gastrointestinal motility in stressed conditions. (R)-Tofisopam has an improved activity for irritable bowl syndrome and is currently in phase IIb clinical trials.Metabolism of racemic tofisopam in microsomal incubations from multiple species was reported previously (Elekes et al, 1981;Tomori et al, 1982Tomori et al, , 1984 and the primary metabolites were identified. These metabolites corresponded to demethylation of one or more of the four tofisopam methoxy groups by cytochrome P450.…”

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confidence: 52%

“…Metabolism of racemic tofisopam in microsomal incubations from multiple species was reported previously (Elekes et al, 1981;Tomori et al, 1982Tomori et al, , 1984 and the primary metabolites were identified. These metabolites corresponded to demethylation of one or more of the four tofisopam methoxy groups by cytochrome P450.…”

mentioning

confidence: 52%

“…Due to the similar polarity of the metabolites, normal phase chromatography was used. Earlier studies on metabolites of tofisopam were unable to obtain clean chromatographic separation of the four potential monodemethylated products (Tomori et al, 1982). Aided by improvement in the commercially available chromatography columns, we were able to develop an LC-MS/MS method for this study to resolve tofisopam and its metabolites in a single injection.…”

Section: Discussionmentioning

confidence: 96%

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In Vitro Prediction and in Vivo Verification of Enantioselective Human Tofisopam Metabolite Profiles

Cameron¹,

Wright²,

Black³

et al. 2007

Drug Metab Dispos

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ABSTRACT:In vitro studies were conducted to elucidate the metabolic profiles of and the enzymes responsible for the metabolism of (R) The use of pure enantiomers as pharmaceuticals has greatly increased the awareness of the effect of chirality on the interactions of small molecules with proteins. In addition to the development of new drugs, several older racemic drugs such as nefopam and thioridazine have been reintroduced as pure enantiomers (Brian, 2001). In cases where one of the enantiomers shows greater activity, the use of pure enantiomers can have key advantages such as improved pharmacokinetics or decreasing nonspecific toxicity problems. There are instances in which toxicity has been linked to one member of a pair of stereoisomers, not necessarily the active isomer (FDA, 1992).-Racemic tofisopam (1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine) is approved in 18 countries including Japan, South Korea, Russia, and Hungary and has been used for many years to treat disorders of the autonomic nervous system (Pakkanen et al., 1980;Hovi-Viander et al., 1985;Andrasi et al., 1987;Nedogoda and Parshev, 2000). Recently the individual enantiomers have been evaluated for their pharmacological activity. Animal models on both (R)-and (S)-tofisopam suggest that they decrease visceral hypersensitivity, have no effect on normal gastrointestinal function, and normalize gastrointestinal motility in stressed conditions. (R)-Tofisopam has an improved activity for irritable bowl syndrome and is currently in phase IIb clinical trials.Metabolism of racemic tofisopam in microsomal incubations from multiple species was reported previously (Elekes et al., 1981;Tomori et al., 1982Tomori et al., , 1984 and the primary metabolites were identified. These metabolites corresponded to demethylation of one or more of the four tofisopam methoxy groups by cytochrome P450. All previous studies detailing tofisopam metabolism were conducted on racemic tofisopam instead of individual enantiomers and did not evaluate the specific enzymes responsible for tofisopam metabolism.In the present study, we present data on the stereoselective metabolism of the individual enantiomers of tofisopam. The concentrations of tofisopam, 50 and 500 ng/ml (Ϸ0.13 and 1.3 M), were chosen to represent clinical concentrations. In vitro studies with recombinant P450 enzymes and with human liver microsomes, (R)-and (S)-tofisopam, showed different metabolite profiles for the two enantiomers. The primary enzymes responsible for generation of the individual metabolites were identified. These in vitro results were confirmed by analyses of samples from human clinical trials. Materials and MethodsChemicals Used. Pure enantiomers of tofisopam, racemic metabolites, and d 6 -tofisopam were synthesized by Cerilliant (Round Rock, TX). Other chemicals were purchased from Sigma Chemical Co. (St. Louis, MO) in the highest purity available. Human liver microsomes (lot 821-1) pooled from 15 individuals (male and female) were obtained from CellzDirect (Aust...

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confidence: 52%

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confidence: 52%

Section: Discussionmentioning

confidence: 96%

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In Vitro Prediction and in Vivo Verification of Enantioselective Human Tofisopam Metabolite Profiles

Cameron¹,

Wright²,

Black³

et al. 2007

Drug Metab Dispos

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“…Thin layer chromatography, reversed and normal phase liquid chromatography, gas liquid chromatography with mass spectrometry or nitrogen phosphorous detection (NPD) were shown to be suitable for the analysis [15][16][17], but none of the GC assays were validated according to requirements of a pharmacokinetic study and GLP regulations. The aim of the present study was to develop and validate a gas chromatographic bioanalytical method for the determination of tofisopam in human plasma for pharmacokinetic study purpose.…”

Section: Introductionmentioning

confidence: 99%

Gas chromatography nitrogen phosphorous detection (GC-NPD) assay of tofisopam in human plasma for pharmacokinetic evaluation

Tóth

Bereczki

Drabant

et al. 2006

Journal of Pharmaceutical and Biomedical Analysis

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Analysis of tofisopam in human serum by column‐switching semi‐micro high‐performance liquid chromatography and evaluation of tofisopam bioequivalency

Baek

Choi

Kim

et al. 2002

Biomedical Chromatography

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A rapid and sensitive column-switching semi-micro HPLC method is described for the direct analysis of tofisopam in human serum. The sample (100 microL) was directly injected onto the precolumn (Capcell Pak MF Ph-1), where unretained proteins were eluted to waste. Tofisopam was then eluted into an enrichment column using 13% acetonitrile in 50 mM phosphate buffer (pH 7.0) containing 5 mM sodium octanesulfonate and subsequently into the analytical column using 43% acetonitrile in 0.1% phosphoric acid containing 5 mM sodium octanesulfonate. The detection limit (2 ng/mL), good precision (CV < or = 4.2%) and speed (total analysis time 24 min) of the present method were sufficient for drug monitoring. This method was successfully applied to a bioequivalence test of two commercial tofisopam tablets.

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Investigation of the metabolites of tofizopam in man and animals by gas-liquid chromatography-mass spectrometry

Cited by 10 publications

References 4 publications

In Vitro Prediction and in Vivo Verification of Enantioselective Human Tofisopam Metabolite Profiles

In Vitro Prediction and in Vivo Verification of Enantioselective Human Tofisopam Metabolite Profiles

Gas chromatography nitrogen phosphorous detection (GC-NPD) assay of tofisopam in human plasma for pharmacokinetic evaluation

Analysis of tofisopam in human serum by column‐switching semi‐micro high‐performance liquid chromatography and evaluation of tofisopam bioequivalency

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