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Detection and Validated Quantification of Toxic Alkaloids in Human Blood

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Detection and Validated Quantification of Toxic Alkaloids in Human Blood JOURNAL OF MASS SPECTROMETRY J. Mass Spectrom. 2007; 42: 621–633 Published online 26 February 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/jms.1191 Detection and validated quantification of toxic alkaloids in human blood plasma – comparison of LC-APCI-MS with LC-ESI-MS/MS Jochen Beyer,1 Frank T. Peters,1 Thomas Kraemer2 and Hans H. Maurer1∗ 1 Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany 2 Forensic Toxicology, Institute of Legal Medicine, Saarland University, D-66421 Homburg (Saar), Germany Received 17 October 2006; Accepted 16 January 2007 Poisonings with toxic plants may occur after abuse, intentional or accidental ingestion of plants. For diagnosis of such poisonings, multianalyte procedures were developed for detection and validated quantification of the toxic alkaloids aconitine, atropine, colchicine, coniine, cytisine, nicotine and its metabolite cotinine, physostigmine, and scopolamine in plasma using LC-APCI-MS and LC-ESI-MS/MS. After mixed-mode solid-phase extraction of 1 ml of plasma, the analytes were separated using a C8 base select separation column and gradient elution (acetonitrile/ammonium formate, pH 3.5). Calibration curves were used for quantification with cotinine-d3, benzoylecgonine-d3, and trimipramine-d3 as internal standards. The method was validated according to international guidelines. Both assays were selective for the tested compounds. No instability was observed after repeated freezing and thawing or in processed samples. The assays were linear for coniine, cytisine, nicotine and its metabolite cotinine, from 50 to 1000 ng/ml using LC-APCI-MS and 1 to 1000 ng/ml using LC-ESI-MS/MS, respectively, and for aconitine, atropine, colchicine, physostigmine, and scopolamine from 5 to 100 ng/ml for LC-APCI-MS and 0.1 to 100 ng/ml for LC-ESI-MS/MS, respectively. Accuracy ranged from −38.6 to 14.0%, repeatability from 2.5 to 13.5%, and intermediate precision from 4.8 to 13.5% using LC-APCI-MS and from −38.3to8.3%for accuracy, from 3.5 to 13.8%, for repeatability, and from 4.3 to 14.7% for intermediate precision using LC-ESI- MS/MS. The lower limit of quantification was fixed at the lowest calibrator in the linearity experiments. With the exception of the greater sensitivity and higher identification power, LC-ESI-MS/MS had no major advantages over LC-APCI-MS. Both presented assays were applicable for sensitive detection of all studied analytes and for accurate and precise quantification, with the exception of the rather volatile nicotine. The applicability of the assays was demonstrated by analysis of plasma samples from suspected poisoning cases. Copyright 2007 John Wiley & Sons, Ltd. KEYWORDS: LC-MS; LC-MS/MS; determination; alkaloids; plasma INTRODUCTION colchicine, coniine, cytisine, nicotine, physostigmine, scopo- lamine. Poisonings with toxic plants may occur after abuse and, For diagnosis and prognosis of such poisonings, ana- intentional or accidental ingestion of plants. The latter is lytical methods for detection and quantification of the particularly frequent among young children, who often respective toxic alkaloids are required in clinical and forensic eat plants which seem attractive to them, e.g. because of toxicology.2 As blood plasma concentrations correlate best colorful fruits. Most toxic ingredients of plants are nitrogen- with the pharmacological/toxicological effects, this sample containing organic compounds, so-called alkaloids. Such matrix should be used for determination whenever possible. alkaloids may act via various pharmacological mechanisms, While many methods have been described for plasma anal- e.g. activation or blocking of receptors or ion channels, caus- ysis of cardiac glycosides,3–7 only few are available for the ing severe or even lethal poisoning. On the basis of the above-mentioned alkaloids. For plasma analysis of aconitine, 1 statistics of a poison control center in Germany, besides procedures were published using GC-MS8,9 or LC-MS/MS,10 cardiac glycosides, the following alkaloids were most fre- for atropine and/or scopolamine using GC-MS8,9,11 or LC- quently involved in plant poisonings: aconitine, atropine, MS(/MS),12–14 for physostigmine (also used as antidote in treatment of atropine and/or scopolamine poisoning) using HPLC with fluorescence15,16 or electrochemical17,18 detec- ŁCorrespondence to: Hans H. Maurer, Department of Experimental and Clinical Toxicology, Saarland University, D-66421 Homburg tion, for nicotine and its main metabolite cotinine using (Saar), Germany. E-mail: [email protected] GC-MS19–21 or LC-MS(/MS),22–28 and finally for colchicine Copyright 2007 John Wiley & Sons, Ltd. 622 J. Beyer et al. Figure 1. Chemical structures of the studied analytes and internal standards. using GC-MS29 or LC-MS(/MS).30–33 However, none of these EXPERIMENTAL methods covered more than two of the above-mentioned Chemicals and reagents alkaloids and methods for plasma analysis of coniine and Aconitine, atropine, colchicine, and scopolamine were cytosine are not available in the literature at all. Therefore, obtained from Fluka (Neu-Ulm, Germany), cytisine from the first aim of the presented study was to develop a multi- ChromaDex (St. Ana, USA), and physostigmine from Koehler analyte procedure for detection and validated quantification Chemie (Alsbach-Haehnlein, Germany). Coniine was a of aconitine, atropine, colchicine, coniine, cytisine, nicotine kind gift of the Institute of Pharmaceutical Biology (Saar- and its metabolite cotinine, physostigmine, and scopolamine bruecken, Germany). Methanolic solutions of cotinine and in blood plasma. The chemical structures of the studied nicotine, as well as the internal standards (IS) cotinine-d3, alkaloids and internal standards are depicted in Fig. 1. Devel- benzoylecgonine-d3, and trimipramine-d3 were obtained opment of an LC-MS-based assay seemed most promising from Promochem (Wesel, Germany). Acetonitrile and water owing to soft ionization, and high selectivity and sensitiv- (both HPLC grade) and all other chemicals (analytical grade) ity. Tandem MS apparatus are more sensitive and selective, were obtained from E. Merck (Darmstadt, Germany). Varian but much more expensive than single stage MS. This raises Bond Elute Certify cartridges (130 mg; 3 ml) were obtained the question whether tandem MS is actually necessary for from Varian (Darmstadt, Germany). detection and quantification of these alkaloids. Therefore, the second aim of the study was to compare a single stage Biosamples versus a tandem MS instrument with respect to selectivity, Human blank plasma samples and blood samples from drug sensitivity, accuracy and precision after identical sample free volunteers were used for development of selectivity preparation. experiments and validation of the procedure. They were Copyright 2007 John Wiley & Sons, Ltd. J. Mass Spectrom. 2007; 42: 621–633 DOI: 10.1002/jms LC-MS and LC-MS/MS of toxic alkaloids 623 obtained from a local blood bank. Applicability experiments an Applied Biosystems 3200 Q TRAP Linear Ion Trap were carried out using plasma samples from poisoning cases Quadrupole Mass Spectrometer with Analyst Software sent to the authors’ laboratory for toxicological analysis. (Version 1.4.1) equipped with a Turbo V Ion Source operated in the electron spray ionization (ESI) mode was used. In Extraction procedure the following, for this system the term tandem MS is Plasma samples (1 ml) were diluted with 2 ml of 5 mM used. aqueous ammonium formate solution adjusted to pH 3 with formic acid. After addition of 0.1 ml of a methanolic solution LC conditions of the IS containing 1000 ng/ml of cotinine-d , 100 ng/ml 3 The following LC conditions were identical in both systems. of benzoylecgonine-d , and 10 000 ng/ml trimipramine-d , 3 3 Gradient elution was performed on a Merck LiChroCART the samples were mixed for 15 s on a rotary shaker, column (125 ð 2 mm internal diameter) with Superspher60 centrifuged for 3 min at 1000 g and loaded on mixed- RP Select B as stationary phase and a LiChroCART 10-2 mode solid-phase extraction (SPE) cartridges previously Superspher 60 RP Select B guard column. The mobile phase conditioned with 1 ml of methanol and 1 ml of purified consisted of 50 mM aqueous ammonium formate adjusted to water. After extraction, the cartridges were washed with 1 ml pH 3.5 with formic acid (eluent A) and acetonitrile (eluent B). of purified water, 1 ml of 0.01 M aqueous hydrochloric acid Before use, the mobile phases were degassed for 30 min in an and 2 ml of methanol. Reduced pressure was applied until ultrasonic bath. During use, the mobile phase was degassed the cartridges were dry, and the analytes were eluted with by the corresponding integrated degasser. Before starting 1 ml of methanol–aqueous ammonia (98 : 2, v/v) into 1.5 ml the analysis, the HPLC systems were equilibrated for 10 min polypropylene reaction vials. The eluates were evaporated with a mixture of 90% of eluent A and 10% of eluent B. The to dryness under a stream of nitrogen at 56 °C. Then, 0.1 ml gradient and the flow rate were programmed as follows: of 5 mM aqueous ammonium formate solution (pH 3) was 0.00–2.00 min 10% B (flow: 0.4 ml/min), 2.01–5.00 min added and the vials were shaken on a rotary shaker for 3 min. gradient increase to 80% B (flow: 0.6 ml/min), 5.01–7.00 min After centrifugation for 2 min at 10.000 g, the solution was 80% B (flow: 0.60 ml/min) 7.01–10.00 min 10% B (flow: transferred to autosampler vials and 10 µl each were injected 0.4 ml/min) for reequilibration of the HPLC column. The into the LC-MS and LC-MS/MS systems. column oven was set at 25 °C.
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