Method development for identification of ketobemidone metabolites in microdialysate samples by coupled-column capillary liquid chromatography–tandem mass spectrometry

Sundström, Ingela; Andrén, Per E.; Westerlund, Douglas

doi:10.1016/j.chroma.2008.02.043

Cited by 11 publications

(5 citation statements)

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“…Many studies on the separation mechanism in LC with a fluorocarbon stationary phase have revealed that “secondary effects”, e.g., absorption to silanol residue on the particulate, and fluorophilicity affect the retention of analytes. − Therefore, LC columns with fluorocarbon stationary phases have been used to separate highly hydrophobic compounds − and structural isomers ,,− that are difficult to separate with conventional RP columns. Furthermore, drug analogues containing some trifluoromethyl structure, a C 1 fluorous unit, have been successfully determined by LC separation using a fluorous-phase column. , Because the fluorous stationary phase can retain fluorous compounds effectively, many examinations based on fluorous interaction have been conducted to collect or remove fluorous compounds ,,− and to investigate the specific separation mechanisms. − , However, to the best of our knowledge, there are no reports on quantitative analysis of fluorous-labeled compounds using a fluorous-phase LC column.…”

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confidence: 99%

Separation-Oriented Derivatization of Native Fluorescent Compounds through Fluorous Labeling Followed by Liquid Chromatography with Fluorous-Phase

et al. 2009

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We have developed a new and simple method based on "fluorous derivatization" for LC of native fluorescent compounds. This method involves the use of a column with a fluorous stationary phase. Native fluorescent analytes with target functional groups are precolumn derivatized with a nonfluorescent fluorous tag, and the fluorous-labeled analytes are retained in the column, whereas underivatized substances are not. Only the retained fluorescent analytes are detected fluorometrically at appropriate retention times, and retained substrates without fluorophores are not detected. In this study, biologically important carboxylic acids (homovanillic acid, vanillylmandelic acid, and 5-hydroxyindoleacetic acid) and drugs (naproxen, felbinac, flurbiprofen, and etodolac) were used as model native fluorescent compounds. Experimental results indicate that the fluorous-phase column can selectively retain fluorous compounds including fluorous-labeled analytes on the basis of fluorous separation. We believe that separation-oriented derivatization presented here is the first step toward the introduction of fluorous derivatization in quantitative LC analysis.

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Separation-Oriented Derivatization of Native Fluorescent Compounds through Fluorous Labeling Followed by Liquid Chromatography with Fluorous-Phase

et al. 2009

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“…In vivo microdialysates from rat administered with ketobemidone, either subcutaneously or by direct infusion in the striatum via a microdialysis probe by reverse microdialysis, were analyzed with coupled capillary LC-and PBA-MS/MS methods. 13 The identifications were performed by comparison of the retention times and tandem mass spectra obtained with those of synthetic standards, as well as from exact mass measurements.…”

Section: Discussionmentioning

confidence: 99%

“…36 Hydroxyketobemidone was present in none of the microdialysates, either in the intact or in oxidized form (a diketone), which also gets trapped on the PBAcolumn. 13 However, hydroxyketobemidone was identified in the rat urine after sc injection of ketobemidone (Fig. 5).…”

Section: Identification Of Hkbmentioning

confidence: 97%

“…The ketobemidone metabolites were identified utilizing analytical methods based on capillary column liquid chromatography tandem mass spectrometry (LC-MS/MS). 13 We used a reversed-phase column packed with highly purified silica-gels bonded with branched fluorocarbonchains. This provides the stationary phase with high-dipole moment that contributes to other possible interactions than hydrophobic, which results in alternative selectivity, suitable for separation of ketobemidone metabolites.…”

Section: Introductionmentioning

confidence: 99%

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In vivo investigation of brain and systemic ketobemidonemetabolism

Sundström

Arts

Westerlund

et al. 2010

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Ketobemidone metabolites have previously been identified in urine and plasma; here we show, for the first time, that norketobemidone and ketobemidone N-oxide are present in in vivo microdialysate from rat brain (striatum) after reverse microdialysis, suggesting striatal metabolism of ketobemidone. Ketobemidone metabolites were also identified in in vivo microdialysate samples from brain and blood, as well as in urine from rats, after subcutaneous administration of ketobemidone. Three Phase I metabolites (norketobemidone, ketobemidone N-oxide and hydroxymethoxyketobemidone) and three Phase II metabolites (glucuronic acid conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone) were identified in the microdialysates after subcutaneous administration. Coupled capillary liquid chromatography tandem mass spectrometry (LC-MS/MS) and SPE (boronate)-MS/MS were utilized for the analysis of the biological samples. The Phase I metabolites were identified by comparing the retention times and tandem mass spectra of the microdialysates with synthetic standards. The Phase II metabolites were identified by determination of exact masses and by comparing the tandem mass spectra of the microdialysates with those of synthetic standards for the aglycones. Hydroxyketobemidone, a catechol-type Phase I metabolite, was selectively isolated by solid-phase boronate-complexation but identified in urine alone. This work demonstrated that the in vivo microdialysis technique in combination with LC-MS/MS can be used to study the local metabolism of a drug in the brain.

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“…A series of papers reported the successful application of microdialysis system to pharmacokinetic study. [12][13][14][15] However, there is no paper to present the application of microdialysis for the preparation of bile samples of sweroside in rat.…”

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Determination of Sweroside in Rat Plasma and Bile for Oral Bioavailability and Hepatobiliary Excretion

Luo

Cao

Wen

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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79 Notes Sweroside (C 16 H 22 O 9 , molecular weight 358.344), an iridoid glycoside, belongs to a large group of natural monoterpenoids with a glucose moiety attached to C-1 in the pyrane ring. It widely exists in plants of many families [1][2][3] and shows a wide variety of biological activities such as hepatoprotective effect, antitumor, antibacterial, antifungal. 4-7)Sweroside is also the main ingredient of purified herbal extracts from the flower buds of Lonicera japonica THUNB. (IGEs-1) which were demonstrated to possess perfect hepatoprotective effect in our preliminary experiments. Since sweroside and its correlative plant extracts have exhibited these pharmacological effects, it would be hopeful that sweroside and IGEs-1 to be developed to some promising preparations of herbal medicinal products (HMPs).Recently, HMPs are getting more common in the main stream in previously skeptical markets such as the United States and United Kingdom. 8) Establishing the pharmacological basis for efficacy of HMPs is a constant challenge. Of particular interest is the question of bioavailability to assess to what degree and how fast compounds are absorbed after administration of HMPs. Of further interest are the elucidation of metabolic pathways, and the assessment of elimination routes and their kinetics. These data become an important issue to link data from pharmacological assays and clinical effects. A better understanding of the pharmacokinetics and bioavailability of HMPs can also help in designing rational dosage regimens. Despite a wide range of research in either sweroside or L. japonica, 9,10) to our best knowledge, there is no information available on the pharmacokinetics of sweroside orally and intravenously administered to investigate its oral bioavailability and hepatobiliary excretion. Moreover, no report has been published to elucidate the metabolites and the metabolic pathways of sweroside.Furthermore, the development of sampling technique has been a focus in vivo experiment.11) Microdialysis system is a sampling technique that can reduce endogenous interference and can be easy to couple with detector for on-line analysis. A series of papers reported the successful application of microdialysis system to pharmacokinetic study.12-15) However, there is no paper to present the application of microdialysis for the preparation of bile samples of sweroside in rat.In the present study, a simple, stable and accurate HPLC-UV method was developed to determine sweroside in rat plasma, urine, feces and bile simultaneously. The method was applied to basic pharmacokinetic and oral bioavailability studies after intravenous administration of sweroside and oral administration of sweroside and IGEs-1. A sampling method through a validated bile microdialysis system coupled with this HPLC-UV determination was developed to evaluate the hepatobiliary excretion of sweroside in rat. ExperimentalPreparation of IGEs-1 and Sweroside The flower buds of Lonicera japonica THUNB. were collected at the middle of May from Mi county, Hena...

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Method development for identification of ketobemidone metabolites in microdialysate samples by coupled-column capillary liquid chromatography–tandem mass spectrometry

Cited by 11 publications

References 51 publications

Separation-Oriented Derivatization of Native Fluorescent Compounds through Fluorous Labeling Followed by Liquid Chromatography with Fluorous-Phase

Separation-Oriented Derivatization of Native Fluorescent Compounds through Fluorous Labeling Followed by Liquid Chromatography with Fluorous-Phase

In vivo investigation of brain and systemic ketobemidonemetabolism

Determination of Sweroside in Rat Plasma and Bile for Oral Bioavailability and Hepatobiliary Excretion

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