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Determination of 8 Diuretics and Probenecid in Human Urine by Gas Chromatography-Mass Spectrometry: Confirmation Procedure

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Determination of 8 Diuretics and Probenecid in Human Urine by Gas Chromatography-Mass Spectrometry: Confirmation Procedure American Journal of Analytical Chemistry, 2012, 3, 320-327 http://dx.doi.org/10.4236/ajac.2012.34044 Published Online April 2012 (http://www.SciRP.org/journal/ajac) Determination of 8 Diuretics and Probenecid in Human Urine by Gas Chromatography-Mass Spectrometry: Confirmation Procedure Olga Zaporozhets, Iuna Tsyrulneva, Mykola Ischenko Taras Shevchenko National University of Kiev, Kiev, Ukraine Email: [email protected] Received February 16, 2012; revised March 15, 2012; accepted March 25, 2012 ABSTRACT A fast and sensitive method for determination of 8 diuretics (acetazolamide, bendroflumethiazide, bumetanide, chlorthali- done, furosemide, hydrochlorothiazide, metolazone, triamterene) and masking agent (probenecid) in human urine using gas-chromatography with mass spectrometric detection is described. The extraction of the substances as function of the nature of organic solvent, mixing time and pH of aqueous phase was studied. The tandem mass spectrometry was used to increase selectivity of diuretics determination due to elimination of background interferences. Fragmentation reac- tions were studied for each compound and their collision energies were optimized to obtain the best selectivity. The results of method’s validation demonstrate its suitability in routine analysis for confirmation purposes. Keywords: Diuretics; Urine; Gas Chromatography; Tandem Mass Spectrometry; Confirmation 1. Introduction trometric detection. Though liquid chromatography with mass spectrometric detection (LC-MS) causes the de- It is known [1] that athletes misuse diuretics for several crease in sensitivity due to the suppression of ionization reasons: to reduce body weight in order to be qualified for a lower weight category, to decrease fluid retention in by biological matrix [4,5] and shift in retention times in body caused by the application of steroids and to reduce case of direct injection of sample [6] it also allows to the concentration of other prohibited substances in urine achieve low detection limits and short time of analysis to avoid positive doping results. International Olympic [7]. Because of relatively high cost of LC-MS this method Committee and World Anti-Doping Agency (WADA) pro- is more preferable for quantative determination of diuret- hibited the use of diuretics in sport. WADA established ics in biological objects and for screening purpose. Gas the requirement for anti-doping laboratories to control chromatography with mass detection (GC-MS) is suit- the presence of these compounds in urine at the level less able for multicomponent, selective and sensitive diuretics or equal to minimum required performance limit (MRPL), determination in human urine, as well as liquid chroma- which is 0.25 µg·ml–1 [2]. Most of the banned substances tography. GC-MS method which includes two-step liq- should not be present at any concentration in the speci- uid-liquid extraction and derivatization was proposed for mens (mainly urine) collected for the analysis. Therefore, quantative determination of 16 diuretics [8]. Long pre- they are often detected only on a qualitative basis. liminary sample preparation of urine limits the use of the Diuretics belong to non-threshold substances, which method in routine analysis. Moreover, this technique means the absence of specific threshold concentration in does not provide high recovery of chlorthalidone and tri- urine. Table 1 shows that diuretics include compounds amterene. At the same time GC-MS demonstrates the which have differences in molecular structures and chemical best results for qualitative determination and for confir- properties [3], and this fact complicates the elaboration mation. of the only method of their extracting from biological The GC-MS method was proposed for confirmation in matrix and their detection at the necessary selectivity [9]. The recovery of diuretics and impeding effect of level. urine matrix and other diuretics were not studied in this According to WADA requirements the only methods work as well as in [10]. Besides, both methods were not of analysis that should be applied at anti-doping labora- validated. Moreover, the technique proposed in [11] is tories are liquid or gas chromatography with mass spec- long lasting which is caused by long retention time. Copyright © 2012 SciRes. AJAC O. ZAPOROZHETS ET AL. 321 Table 1. General characteristics of diuretics. рКа рКа Name Structure Name Structure рКа1 рКа2 рКа1 рКа2 Cl O S NH HN2 N N NH2 2 O N Triamterene N 6.2 - Indapamide H 8.8 - N O NH2 N Cl O NH O S 2 NN O O Acetazolamide N S 7.4 9.1 Chlorthalidone HO 9.4 - H S O NH NH 2 O H N Cl O HN Cl Chlorothiazide N O 6.7 9.5 Furosemide 3.9 - S S O NH O O O O 2 S NH HO 2 O H N Cl NH Hydrochlorothiazide HN O 7.9 9.2 Bumetanide 3.6 7.7 S S O O NH O O 2 O O S NH2 OH O Cl H N Cl HO Cl O S N Trichlormethiazide HN O 7 10 Probenecid 3.4 - S S O O O O NH O 2 Cl O F Cl H F Ethacrinic acid Bendroflumethiazide N 8.5 - 3.5 - F HO (Internal Standard) O HN O S S O O O O NH 2 H N Cl Metolazone N O 9.7 - S NH O O 2 Despite the great number of methods proposed, gas or detection. liquid chromatography with mass spectrometric detection do not always provide the necessary selectivity towards 2. Experimental Procedure the urine components [10,12]. In case of liquid chroma- 2.1. Preparation of Reagent Solutions tography, the use of tandem mass-spectrometry allowed to pass over these problems and to ensure the satisfactory Stock standard solutions were prepared for 12 diuretic result [13-15]. drugs (acetazolamide, bendroflumethiazide, bumetanide, Despite liquid chromatography is more preferable for chlorthalidone, chlorothiazide, ethacrinic acid, furosemide, screening purposes, gas chromatography with mass de- hydrochlorothiazide, indapamide, metolazone, triamterene, tection demonstrates the best results for confirmation. trichlormethiazide) and a masking agent (probenecid) (all According to WADA requirements the optimal method by SIGMA, St. Louis, MO, USA) by dissolving in metha- for confirmation of presence of diuretics is the method nol at concentration of 1.0 mg·ml–1. different from the screening method. Therefore, the goal Diethyl ether, ethyl acetate, isopropanol, acetone (Merck, of the present work was to develop a method of confir- Darmstadt, Germany) and methanol (SIGMA, St. Louis, mation of presence of diuretics and probenecid in urine MO, USA) had a qualification “for chromatography”. by gas chromatography with tandem mass spectrometric Methyl iodide with purity 99% (SIGMA, St. Louis, MO, Copyright © 2012 SciRes. AJAC 322 O. ZAPOROZHETS ET AL. USA), sodium sulfate (Merck, Darmstadt, Germany) were The top layer was totally transferred to a 10 ml glass used without further purification, potassium carbonate tubes. Solutions were evaporated in nitrogen stream at (Merck, Darmstadt, Germany) was used after calcination 40˚C (for solvents based on diethyl ether) or 80˚C (for in oven. Hydrochloric acid and sodium hydroxide were solvents based on ethyl acetate) to obtain solid residue, prepared by dilution of the concentrated initial solution the tubes were cooled to room temperature. The deri- (Merck, Darmstadt, Germany). vatization (methylation by methyl iodide in acetone in an alkaline environment) was performed according to [16]. 2.2. Instruments and Materials Afterwards the samples were immediately sent to gas- chromatographic analysis. The degree of substances re- Gas chromatograph Varian 3800 (Australia) equipped with covery from matrix achieved by liquid-liquid extraction an automatic sample injector system Combipal and Fac- was investigated at a concentration of 0.9 MRPL (0.225 torFour Capillary Column VF-DA 12 m, 0.20 mm I.D. –1 µg·ml ). The mixture of standard diuretics and IS were for mass spectrometric determination of narcotic drugs added to the urine samples and sample preparation was and pharmaceuticals. Mass spectrometer Varian 1200 performed by the method described. Simultaneously, the (Australia), directed by computer system of data proc- derivatization of mixture of diuretics standards with the essing Varian MsWorkstation 6.9, with a system of three same concentration was conducted. All samples were quadruples. Auxiliary equipment: thermostat VLM EC1 analyzed by chromatographic-mass spectrometric method. (Germany), evaporator in nitrogen stream Liebisch (Ger- The recovery degree was calculated by taking the ratio of many), centrifuge OPN-3Y4.2 (Russia), shaker Heidolph peak height obtained at the retention time for the analyte Vibramax 110 (Germany), oven Binder (Germany), pH- of interest compared to that obtained from an IS in spiked meter inoLab pH level 1 (Germany), analytical balance urine and mixture of standards. KERN ABS (Germany), pipettes of adjustable volume Eppendorf (Germany) 0 - 20 µl, 20 - 200 µl, 100 - 1000 µl, 2.5. Method Validation 500 - 5000 µl. To determine all parameters (capability to identification, 2.3. Instrumental Parameters selectivity, detection limit), that are necessary for suit- ability of verification in accordance with ISO/IEC 17025: Instrumental parameters of chromatographic determina- 2006 [17], the investigation was performed. Linearity, tion: carrier gas—helium, flow rate—1 ml·min–1, injector accuracy and precision were not examined since the me- temperature—290˚C, injector mode—split 20; volume of thod is intended for confirmation and is not intended for sample injected—2 µl; flushing liquid—acetone, source temperature—225˚C, interface temperature—250˚C; SIM quantitative determination of diuretics, as established in Width—0.7; Scan Time—0.2 s; start of the ion current [17,18]. Therefore more consideration was given to defi- registration—5.3 min. Instrumental parameters of tandem nite identification of the analyte in urine. mass spectrometry: auxiliary gas pressure (argon) on the second quadruple—2.10 - 1.65 mTorr, electron energy at Table 2. Characteristic ions of diuretics in Selected Ion Mo- nitoring mode. the source—20 eV. Registration mode: selected ion moni- toring (SIM) or multiple reaction monitoring (MRM).
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