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Quantitative Analysis of 33 Benzodiazepines, Metabolites and Benzodiazepine-Like Substances in Whole Blood by Liquid Chromatography–(Tandem) Mass Spectrometry

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Quantitative Analysis of 33 Benzodiazepines, Metabolites and Benzodiazepine-Like Substances in Whole Blood by Liquid Chromatography–(Tandem) Mass Spectrometry Journal of Chromatography B, 811 (2004) 13–20 Quantitative analysis of 33 benzodiazepines, metabolites and benzodiazepine-like substances in whole blood by liquid chromatography–(tandem) mass spectrometry B.E. Sminka,∗, J.E. Brandsmaa, A. Dijkhuizena, K.J. Lusthofa, J.J. de Gierb, A.C.G. Egbertsb, D.R.A. Ugesc a Department of Toxicology, Netherlands Forensic Institute, P.O. Box 3110, 2280 GC Rijswijk, The Netherlands b Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508 TB Utrecht, The Netherlands c Department of Pharmacy, Toxicology and Forensic Medicine, State University and University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands Received 20 November 2003; accepted 24 March 2004 Abstract A quantitative method using high-performance liquid chromatography–mass spectrometry (LC–MS, ion trap) after matrix supported liquid–liquid extraction is described for the simultaneous determination in whole blood of 33 benzodiazepines including metabolites and benzodiazepine-like substances. The limits of detection (LOD) range from 0.0001 to 0.0126 mg/l. Linearity is satisfactory for all compounds. The extraction recoveries for the benzodiazepines in whole blood are between 60 and 91%, desmethyldiazepam, OH-bromazepam and brotizolam excepted. Selectivity, accuracy and precision are satisfactory for clinical and forensic purposes. © 2004 Elsevier B.V. All rights reserved. Keywords: Benzodiazepines; Whole blood analysis; Drugs and driving 1. Introduction ease may be at increased risk of respiratory depression [5]. The use of benzodiazepines is also associated with an in- Benzodiazepines are substances with a broad range of creased risk of a road-traffic accident [6]. Large doses are therapeutic uses; they have sedative-hypnotic, muscle re- rarely fatal unless other drugs are taken concomitantly. Due laxant, anxiolytic, anticonvulsant but also addictive effects to their wide variety of uses and their relative safety, benzodi- [1,2]. Since the first benzodiazepines were introduced to the azepines and benzodiazepine-like substances (e.g. zopiclone) market in 1960, there has been an evolution in the devel- are frequently used. Analysis of benzodiazepines, their ac- opment of these drugs toward compounds with less active tive metabolites and benzodiazepine-like substances in blood metabolites, shorter action and faster clearance. There are samples may be indicated in a lot of forensic cases such as more than twenty benzodiazepines in use in The Netherlands driving under the influence of drugs, cases of date-rape or [3]. The benzodiazepines are relatively safe drugs with mild violent crime and cases of unknown causes of death. In The side effects. However, elderly patients are at increased risk Netherlands, autopsy cases excluded, samples are collected of benzodiazepine induced psychomotor impairment (bro- by physicians and shipped by mail to The Netherlands Foren- ken hips by falling [4]) and patients suffering a lung dis- sic Institute in containers with sodium fluoride as preserva- tive, which makes it impossible to obtain plasma or serum ∗ Corresponding author. Tel.: +31 70 4135 772; fax: +31 70 4135 452. by centrifuging. As a consequence, the analytical methods E-mail address: b.smink@nfi.minjus.nl (B.E. Smink). must be suitable for the analysis of whole blood samples. The 1570-0232/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jchromb.2004.03.079 14 B.E. Smink et al. / J. Chromatogr. B 811 (2004) 13–20 large number of possibly present benzodiazepines, metabo- Germany). Solvents used were methanol (Rathburn, Brun- lites and benzodiazepine-like substances must be consid- schwig Chemie B.V., Amsterdam, The Netherlands, HPLC- ered. Screening methods involving high-performance liquid grade), acetonitrile (Merck, VWR Amsterdam, The Nether- chromatography with diode-array detection (HPLC–DAD) lands, HPLC-grade Lichrosolv), ammonia solution 25% or gas chromatography in combination with mass spectrom- (m/v) (Merck, pro analyse), formic acid (Merck, pro analyse) etry (GC–MS) may often be not sensitive enough for forensic and t-butylmethylether (Merck, Suprasolv). The ammonia or clinical purposes [7]. solution (approximately 0.005 M) was made up by diluting Until now, we have used two analytical methods to analyse 0.75 ml ammonia 25% (m/v) to 2000 ml with distilled water. benzodiazepines, metabolites and benzodiazepine-like sub- The formic acid solution (approximately 0.006 M) was made stances in blood. One method, using HPLC–DAD to deter- up by diluting 0.45 ml formic acid 100% (v/v) to 2000 ml mine a limited number of benzodiazepines with medium to with distilled water. high blood concentrations in the therapeutic range such as di- ChemElut® cartridges (Varian, Middelburg, The Nether- azepam and oxazepam, and another method, using LC–MS lands: pre-buffered, pH 9) were used for the sample prepara- to analyse benzodiazepines with low (therapeutic) blood con- tion of whole blood. centrations like flunitrazepam. The aim of this study was to Human blood was obtained after informed consent, from develop a new method that is suited for all available benzodi- donors of the blood bank in Leiden and screened for the pres- azepines with low limits of detection (LOD). In this article, ence of benzodiazepines by HPLC–DAD and LC–MS(MS). we present a validated method that is capable of analysing 33 benzodiazepines, metabolites and benzodiazepine-like sub- 2.2. Sample preparation stances in whole blood samples by using LC in combination with alternate MS and MS–MS detection. The selection of Blood samples, spiked with all compounds and 50 ␮lofthe the tested substances and metabolites is based on the avail- internal standard solution, were applied onto the ChemElut® ability in The Netherlands and the pharmacological activity cartridges, followed by 1.5 ml water. The samples were eluted [1,3]. from the cartridges with 4 ml t-butylmethylether and after a pause of 20 min with another 2 × 4ml t-butylmethylether. Evaporation of the eluate was performed by using an Auto- 2. Experimental matic Environmental Speedvac AES2000 (Savant) with dry- ing rate “high” (50 ◦C) for 35 min. The residue was redis- 2.1. Chemicals and reagents solved in 100 ␮l methanol:water (40:60). Chemicals were obtained from Alltech (State College, 2.3. Equipment PA 16801 USA: norchlordiazepoxide), Aventis Pharma (Hoevelaken, The Netherlands: clobazam, desmethyl- The LC–MS system consisted of a TSP Spectra SYSTEM clobazam, loprazolam), Boehringer Ingelheim (Alkmaar, (Finnigan, Breda, The Netherlands), including a SN4000 con- The Netherlands: brotizolam), Bufa (Uitgeest, The Nether- troller, a vacuum degasser (SCM 1000), a pump (P4000) and lands: diazepam, flunitrazepam, lorazepam, oxazepam, an auto sampler (AS3000), connected to an ion trap mass temazepam), Cerilliant (Austin TX, USA: alprazolam, spectrometer (LCQ, Finnigan). hydroxy-alprazolam, bromazepam, aminoflunitrazepam, In order to determine the influence of the interface on the norflunitrazepam, flurazepam, desalkylflurazepam, sensitivity, standards (1000 mg/l diluted in acetonitrile:water lormetazepam, midazolam, hydroxy-midazolam, desmethyl- = 10:90) were analyzed by using atmospheric pressure chemi- diazepam, triazolam, hydroxy-triazolam), Hoffman-La cal ionization (APCI)–LC–MS as well as ESI–LC–MS. From Roche (acetamidonitrazepam, chlordiazepoxide, de- all tested benzodiazepines, the signal-to-noise ratios from the moxepam, OH-ethylflurazepam, desmethylmedazepam), different interfaces were compared. The interface used in the Lorex Synthelabo (Maidenhead, UK: zolpidem), Roche final procedure is atmospheric pressure chemical ionization. (Almere, The Netherlands: hydroxy-bromazepam, acetami- For the analysis of benzodiazepines, conditions were op- doclonazepam, aminoclonazepam) and Sigma–Aldrich timized. Chromatographic data were acquired and processed Chemie B.V. (Zwijndrecht, The Netherlands: clonazepam, using X-caliburTM 1.2 software (Finnigan). nitrazepam, zopiclone). Stock solutions were prepared by dissolving 10 mg (ac- 2.4. Chromatography curately weighed) of the compound in 10 ml of methanol. These solutions were stored at −20 ◦C. Working standards In order to optimize the separation, two different col- were diluted in methanol. The concentrations of the work- umn materials and four different solvents were tested. Eight ing standards were approximately 0.1 mg/l methanol for all column–solvent combinations were tested by analysing stan- compounds. dards in methanol in order to achieve the best separation The solution of the internal standard (methylbro- of the compounds. The columns tested were the Xterra mazepam), was obtained from Chromsystems (Munchen, MS C-18 (150 mm × 2.1 mm, 3.5 ␮m PS, Waters) and the B.E. Smink et al. / J. Chromatogr. B 811 (2004) 13–20 15 Xterra RP C-18 (150 mm × 2.1 mm, 3.5 ␮m PS, Waters). tion was calculated for a signal-to-noise ratio of 10. Extrac- The injection volume was 50 ␮l. Chromatography was per- tion recovery, expressed as a percentage, was determined by formed by using a flow-rate of 0.2 ml/min and a column assaying spiked blood samples 10 times at a concentration temperature of 30 ◦C. The linear gradients used were acetoni- level of 1.0 mg/l. The extraction recovery was determined by trile/ammonia approximately 0.005 M (pH 10, 25–65% (v/v) comparing the peak heights of extracted blood samples with acetonitrile), acetonitrile/formic acid approximately 0.006 M the peak heights of standards prepared in methanol. Linear- (pH 3, 25–60% (v/v) acetonitrile), methanol/ammonia ap- ity was estimated by assaying calibration curves consisting proximately 0.005 M (pH 10, 45–90% (v/v) methanol) and of a blank blood sample and 10 spiked blood samples (0.005; methanol/formic acid approximately 0.006 M (pH 3, 30–60% 0.01; 0.02; 0.05; 0.1; 0.2; 0.5; 1.0; 2.0; 5.0 mg/l). Linear re- (v/v) methanol). gression has been used to estimate the slopes and the inter- The optimized method used a Xterra MS C-18 col- cepts. Deviation from linearity was investigated by consecu- umn (150 mm × 2.1 mm, 3.5 ␮m PS, Waters, Etten-Leur, tively including an extra datapoint in the calibration curve and The Netherlands).
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