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Rapid Analysis of Pharmaceuticals and Excreted Xenobiotic and Endogenous Metabolites with Atmospheric Pressure Infrared MALDI Mass Spectrometry

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Rapid Analysis of Pharmaceuticals and Excreted Xenobiotic and Endogenous Metabolites with Atmospheric Pressure Infrared MALDI Mass Spectrometry Metabolomics (2008) 4:297–311 DOI 10.1007/s11306-008-0120-8 ORIGINAL ARTICLE Rapid analysis of pharmaceuticals and excreted xenobiotic and endogenous metabolites with atmospheric pressure infrared MALDI mass spectrometry Bindesh Shrestha Æ Yue Li Æ Akos Vertes Received: 9 March 2008 / Accepted: 9 July 2008 / Published online: 20 July 2008 Ó Springer Science+Business Media, LLC 2008 Abstract Atmospheric pressure (AP) infrared (IR) MS Mass spectrometry matrix-assisted laser desorption/ionization (MALDI) mass DESI Desorption electrospray ionization spectrometry (MS) was demonstrated for the rapid direct DART Direct analysis in real time analysis of pharmaceuticals, and excreted human metabo- DAPCI Desorption atmospheric pressure chemical lites. More than 50 metabolites and excreted xenobiotics ionization were directly identified in urine samples with high LAESI Laser ablation electrospray ionization throughput. As the water content of the sample was serving DIOS Desorption ionization on silicon as the matrix, AP IR-MALDI showed no background LISMA Laser-induced silicon microcolumn arrays interference in the low mass range. The structure of tar- CAD Collision activated dissociation geted ions was elucidated from their fragmentation pattern LOD Limit of detection using collision activated dissociation. The detection limit m/z Mass-to-charge ratio for pseudoephedrine was found to be in the sub-femtomole range and the semi-quantitative nature of the technique was tentatively demonstrated for a metabolite, fructose, by 1 Introduction using a homologous internal standard, sucrose. A potential application of AP IR-MALDI for intestinal permeability Advances in combinatorial chemistry have lead to a studies was also explored using polyethylene glycol. remarkable increase in the synthesis of drug candidates. As a result high-throughput analytical techniques are needed Keywords Mass spectrometry Á Pharmaceuticals Á for their detection and structural identification during Human metabolomics Á Metabolites Á Matrix-assisted synthesis and in biological activity assessment (Triolo et al. laser desorption ionization Á MALDI Á Atmospheric 2001). Mass spectrometry is a well established tool for the pressure MALDI Á Infrared MALDI Á Intestinal analysis of xenobiotic and endogenous metabolites (Dett- permeability mer et al. 2007; Glassbrook et al. 2000; Nicholson et al. 2002; Siuzdak 1994). Many other non-mass spectrometric Abbreviations techniques, such as infrared spectrometry (Blanco et al. AP Atmospheric pressure 1998; Guimara˜es et al. 2006; MacDonald and Prebble IR Infrared 1993), Raman spectroscopy (Strachan et al. 2007), tera- MALDI Matrix-assisted laser desorption/ionization hertz imaging (Kawase et al. 2003), fluorescence (MALDI) spectroscopy (Moreira et al. 2005) and nuclear magnetic resonance (Balchin et al. 2005; Maher et al. 2007; Pop- chapsky and Popchapsky 2001), provide useful and B. Shrestha Á Y. Li Á A. Vertes (&) complementary information on their chemical composition. Department of Chemistry, W. M. Keck Institute for Proteomics Mass spectrometry gives unique insights into metabolism Technology and Applications, George Washington University, Washington, DC 20052, USA due to its high sensitivity and the ability to selectively e-mail: [email protected] identify these molecules through fragmentation studies. 123 298 B. Shrestha et al. The detection of metabolites for medical diagnosis and for pharmaceutical synthesis also contain significant amounts clinical or forensic toxicology is dominated by hyphenated of water. Atmospheric pressure (AP) IR-MALDI could approaches (Bowers 1997; Dettmer et al. 2007; Papac and enable the rapid direct analysis of these samples with little Shahrokh 2001), such as gas chromatography-MS (Wol- or no sample preparation (Laiko et al. 2000; Laiko et al. thers and Kraan 1999), liquid chromatography-MS 2002). (Kostiainen et al. 2003; Niessen 1999) and capillary elec- Soft laser desorption ionization techniques use a focused trophoresis-MS (Smyth and Rodriguez 2007). The laser beam to ionize the sample. This local analysis capa- conventional mass spectrometric methods for drug and bility enables chemical imaging of biological tissues to metabolite studies require extensive sample preparation spatially map the distribution of pharmaceutical com- and/or extended analysis time. pounds in various tissues (Bunch et al. 2004; Hsieh et al. Sample preparation and analysis time can be reduced by 2006; Reyzer et al. 2003). In addition to providing an using ambient ion sources. A variety of recently introduced attractive alternative for imaging the distribution of phar- methods, including desorption electrospray ionization maceuticals and their metabolites in tissue without the need (DESI) (Chen et al. 2005; Kauppila et al. 2006; Leuthold to apply an external matrix, AP IR-MALDI could also et al. 2006; Takats et al. 2004), direct analysis in real time enable high-throughput analysis of samples in a multi-well (DART) (Cody et al. 2005), desorption atmospheric pressure plate under ambient conditions. We have recently descri- chemical ionization (DAPCI) (Takats et al. 2005), extractive bed the utility of AP IR-MALDI for the analysis and electrospray ionization (EESI) (Chen et al. 2006b; Chen et al. imaging of plant metabolites directly from tissue samples 2007), plasma-assisted desorption/ionization (PADI) (Li et al. 2007, 2008). The present study explores the use of (Ratcliffe et al. 2007), and laser ablation electrospray AP IR-MALDI for the analysis of selected pharmaceuticals ionization (LAESI) (Nemes and Vertes 2007), have dem- in their commercial formulations, and the related metabo- onstrated the capability of ambient analysis of complex lites in human urine. samples without extensive sample preparation. A recent comparative study of DESI, DART, and DAPCI has shown that the three methods provide complementary information 2 Materials and methods for a range of pharmaceuticals (Williams et al. 2006). Since its inception in 1988, matrix-assisted laser 2.1 AP IR-MALDI instrumentation desorption/ionization (MALDI) mass spectrometry (MS) has been used as a tool for analysis of large biomolecules All the experiments were carried out with an orthogonal and synthetic polymers (Karas and Hillenkamp 1988; Ta- acceleration time-of-flight mass spectrometer, Q-TOF naka et al. 1988). The application of MALDI MS for low Premier (Waters Co., Milford, MA), utilizing a custom mass compounds of biological interest (Duncan et al. 1993; made atmospheric pressure MALDI interface described Lidgard and Duncan 1995), such as carbohydrates, amino elsewhere (Li et al. 2007, 2008). The sample deposited on a acids etc., has been recently reviewed (Cohen and Gusev stainless steel target was ionized by a Nd:YAG laser-driven 2002). The use of MALDI for the analysis of small mol- optical parametric oscillator (Opotek, Carlsbad, CA) run- ecules is primarily limited by often overwhelming ning at 2.94 lm wavelength, 10 Hz repetition rate, and 5 ns background interference from the matrix molecules in the pulse width. The laser beam was steered and aligned by low mass region. To overcome this limitation, Siuzdak and SiO protected gold mirrors (Thorlabs, Newton, NJ) with coworkers introduced a matrix-free approach called [97.5% reflectivity to a plano-convex calcium fluoride desorption ionization on silicon (DIOS) (Wei et al. 1999). lens with 50 mm focal length (Infrared Optical Products, DIOS (Go et al. 2003) and other matrix-free laser ioniza- Farmingdale, NY). The laser beam was focused with the tion methods, e.g., laser-induced silicon micro-column lens to the target surface at an approximately 45° incidence arrays (LISMA) (Chen and Vertes 2006), have demon- angle producing an elliptical laser spot with *250 9 650 strated excellent sensitivity for small molecule analysis. lm2 dimensions. The average pulse energy was 240 ± 10 With these methods, however, the direct analysis of bio- lJ, which corresponded to a fluence of 0.20 ± 0.02 J/cm2. logical fluids has not been demonstrated. The target was placed on a 3-axis translation stage for At mid-infrared laser wavelengths (2.94 lm), a non- sample positioning and geometry optimization. The dis- interfering MALDI matrix, such as ice or water, can also be tance between the mass spectrometer inlet orifice and the used to analyze proteins (Berkenkamp et al. 1996) and target surface was set to *2 mm to maximize the ion small metabolites (Li et al. 2008). As most cells and tissues signal intensity without producing an electrical breakdown contain 60–90% water, it is an attractive matrix to study or adversely effecting the focusing. A pulsed voltage of ± biological samples. Many pharmaceutical formulations 3.0 kV was applied to the target in order to improve the ion (e.g., syrups, ointments and gels) and mother liquors in collection efficiency. In this technique, known as pulsed 123 Rapid analysis of pharmaceuticals 299 dynamic focusing, the high voltage on the target is reduced restrictions except for total abstinence from alcoholic to zero after *10 ls as expanding plume approaches the beverages, and smoking 24 h prior to the administration of inlet orifice of the mass spectrometer. This results in the the medicine. The urine samples were collected at various optimal combination of electric field and aerodynamic flow times before and after (2.5 h, and 24 h) the single-dose oral for ion collection (Tan et al. 2004). Typically, the mass administration of a gelatin capsule containing the following spectrometer orifice was heated
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