Screening, confirmation and quantitation of diuretics in urine for doping control analysis by high-performance liquid chromatography–atmospheric pressure ionisation tandem mass spectrometry

Thieme, Detlef; Grosse, Joachim; Lang, R.; Mueller, Robert; Wahl, Anika

doi:10.1016/s0378-4347(01)00058-5

Cited by 71 publications

(38 citation statements)

References 16 publications

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“…Product ion spectra of compounds related to testosterone (8)(9)(10)(11)(12) contain abundant fragments at m/z 97 and 109 (Table 1), the proposed generation of which was described for testosterone by Williams et al 28 This particular dissociation pathway is valid also for 17-substituted testosterone analogues such as 8-11, which yield abundant fragments originating from A-and B-ring cleavages. However, to a smaller extent, also fragment ions generated by D-ring dissociation are found in product ion spectra of 8-11.…”

Section: Steroids With 3-keto-4-ene Nucleusmentioning

confidence: 83%

Characterization of chemically modified steroids for doping control purposes by electrospray ionization tandem mass spectrometry

et al. 2005

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The discovery of the designer steroid tetrahydrogestrinone (THG) in elite athletes' doping control samples in 2003 demonstrated the availability of steroid derivatives prepared solely for doping purposes. Modern mass spectrometers utilizing electrospray ionization and collisionally activated dissociation (CAD) of analytes allow the structural characterization of steroids and their derivatization sites by the elucidation of fragmentation behaviors. A total of 21 steroids comprising either a 4,9,11-triene, a 3-keto-4-ene or a 3-keto-1-ene nucleus were investigated regarding their dissociation pathways, deuterated analogues were synthesized and fragmentation routes were postulated, permitting the identification of steroidal structures and modifications. Compounds based on a 4,9,11-triene steroid with an ethyl residue at C-13 (gestrinone analogues) generate abundant fragment ions at m/z 241 and 199, whereas the substitution of the C-13 ethyl group by a methyl residue (trenbolone analogues) results in a shift of m/z 241 to 227. Substances related to testosterone with a 3-keto-4-ene structure give rise to abundant fragment ions at m/z 109 and 97 whereas steroids with a 3-keto-1-ene nucleus eliminate the A-ring including the carbons C-1-C-4, in addition to C-19 that is proposed to migrate from C-10 to C-1 under CAD conditions.

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Section: Steroids With 3-keto-4-ene Nucleusmentioning

confidence: 83%

Characterization of chemically modified steroids for doping control purposes by electrospray ionization tandem mass spectrometry

et al. 2005

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“…LC/MS, however, allows for the direct separation and identification without a preliminary derivatization step. Recently several methods have been reported for the identification of diuretics by LC/MS (n) (Garbis et al, 1998;Sanz-Nebot et al, 2001;Thieme et al, 2001). The aim of this study was to validate a screening method for 18 diuretics and probenecid in human urine following Eurachem validation guidelines (Eurachem Working Group, 1998).…”

Section: Introductionmentioning

confidence: 99%

Screening for 18 diuretics and probenecid in doping analysis by liquid chromatography–tandem mass spectrometry

Deventer

Delbeke

Roels

et al. 2002

Biomedical Chromatography

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A fast and selective liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for the screening of 18 diuretics and probenecid in human urine is presented. Analyses were performed on a LCQ-Deca instrument equipped with ESI-interface using scan by scan polarity changing. All diuretics and probenecid were separated in less than 20 min after liquid-liquid extraction with ethyl acetate. The LOD for all substances was 100 ng/mL or better. The method was applied to detect diuretics after the oral administration of several drugs including hydrochlorothiazide, bumetanide, spironolactone, furosemide, amiloride, triamterene, chlortalidone and epithizide. All diuretics could be detected for periods up to 96 h after the intake of therapeutic amounts.

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“…For instance, the diuretic effect of chlorothiazide (6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) was increased by a factor of 10 by the hydration of its N-3¢C-4 double bond to hydrochlorothiazide (6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide) [11][12][13], and the substitution of a 2,6-dimethylanilide residue by a 2,6-dimethylpiperidyl group and a hydroxyl group by a hydrogen changes the diuretic agent xipamide to clopamide ( Figure 1). The identification of structural deviations can be accomplished by means of different ionization techniques such as electron impact ionization (EI) [14 -16] or electrospray ionization (ESI) [17][18][19], followed by MS-MS experiments with efficient collision-activated dissociation (CAD), generating structure informative fragment ions of the analytes. With negative electrospray ionization, the location of hydrogen abstraction has a significant influence on the subsequent dissociation of the deprotonated molecule, and thus on the fragmentation pattern, which provides fundamental information about the molecule.…”

mentioning

confidence: 99%

Effect of the location of hydrogen abstraction on the fragmentation of diuretics in negative electrospray ionization mass spectrometry

Thevis

Schänzer

Schmickler

2003

J. Am. Soc. Mass Spectrom.

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The diuretic agents bumetanide, xipamide, indapamide, and related compounds were investigated in order to determine the effect of different ionization sites on their collisionally activated dissociation and the corresponding fragmentation pathways. Therefore, analytes were selectively alkylated, and structural analogues as well as deuterium labeled compounds synthesized, which contain a reduced number of ionizable hydrogen atoms. Thus, specific hydrogen abstractions and their correlated dissociation routes of the negatively charged molecules were eliminated, providing evidence for the influence of the location of ionization on product ion spectra. Fragment ions such as m/z 78 indicate ionization at the commonly present sulfamoyl residue of diuretics but does not exclude additional ionization sites. Product ion spectra of the investigated diuretic agents proved to be composed by fragmentations initiated from different hydrogen abstractions. Moreover, the generation of radical anions by collision-activated dissociation of even-electron precursor ions was observed, the generation of which is discussed by proposed fragmentation pathways. (J Am Soc Mass Spectrom 2003, 14, 658 -670)

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Screening, confirmation and quantitation of diuretics in urine for doping control analysis by high-performance liquid chromatography–atmospheric pressure ionisation tandem mass spectrometry

Cited by 71 publications

References 16 publications

Characterization of chemically modified steroids for doping control purposes by electrospray ionization tandem mass spectrometry

Characterization of chemically modified steroids for doping control purposes by electrospray ionization tandem mass spectrometry

Screening for 18 diuretics and probenecid in doping analysis by liquid chromatography–tandem mass spectrometry

Effect of the location of hydrogen abstraction on the fragmentation of diuretics in negative electrospray ionization mass spectrometry

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