Liquid chromatography-mass spectrometry in the study of the metabolism of drugs and other xenobiotics

Oliveira, Elder Eldervitch Carneiro de; Watson, David

doi:10.1002/1099-0801(200010)14:6<351::aid-bmc28>3.0.co;2-2

Cited by 69 publications

(46 citation statements)

References 104 publications

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“…Most of the analytic work in this study was performed on an LC-MS system that represents a powerful tool in identifying and characterizing xenobiotic metabolites (Oliveira and Watson 2000). With no analytic standards Fig.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of acetaminophen (paracetamol) in plants—two independent pathways result in the formation of a glutathione and a glucose conjugate

Huber¹,

Bartha²,

Harpaintner³

et al. 2009

Environ Sci Pollut Res

120

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Background, aim, and scope Pharmaceuticals and their metabolites are detected in the aquatic environment and our drinking water supplies. The need for high quality drinking water is one of the most challenging problems of our times, but still only little knowledge exists on the impact of these compounds on ecosystems, animals, and man. Biological waste water treatment in constructed wetlands is an effective and low-cost alternative, especially for the treatment of non-industrial, municipal waste water. In this situation, plants get in contact with pharmaceutical compounds and have to tackle their detoxification. The mechanisms for the detoxification of xenobiotics in plants are closely related to the mammalian system. An activation reaction (phase I) is followed by a conjugation (phase II) with hydrophilic molecules like glutathione or glucose. Phase III reactions can be summarized as storage, degradation, and transport of the xenobiotic conjugate. Until now, there is no information available on the fate of pharmaceuticals in plants. In this study, we want to investigate the fate and metabolism of N-acetyl-4-aminophenol (paracetamol) in plant tissues using the cell culture of Armoracia rusticana L. as a model system. Materials and methods A hairy root culture of A. rusticana was treated with acetaminophen in a liquid culture. The formation and identification of metabolites over time were analyzed using HPLC-DAD and LC-MS n techniques. Results With LC-MS technique, we were able to detect paracetamol and identify three of its metabolites in root cells of A. rusticana. Six hours after incubation with 1 mM of acetaminophen, the distribution of acetaminophen and related metabolites in the cells resulted in 18% paracetamol, 64% paracetamol-glucoside, 17% paracetamol glutathione, and 1% of the corresponding cysteine conjugate. Discussion The formation of two independently formed metabolites in plant root cells again revealed strong similarities between plant and mammalian detoxification systems. The detoxification mechanism of glucuronization in mammals is mirrored by glucosidation of xenobiotics in plants. Furthermore, in both systems, a glutathione conjugate is formed. Due to the existence of P450 enzymes in plants, the formation of the highly reactive NAPQI intermediate is possible. Conclusions In this study, we introduce the hairy root cell culture of A. rusticana L. as a suitable model system to study the fate of acetaminophen in plant tissues. Our first results point to the direction of plants being able to take up and detoxify the model substrate paracetamol. These first findings underline the great potential of using plants for waste water treatments in constructed wetlands. Recommendations and perspectives This very first study on the detoxification of a widely used antipyretic agent in plant tissues again shows the flexibility of plant detoxification systems and their potential in waste water treatment facilities. This study covers only the very first steps of acetaminophen detoxification in plants; s...

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Section: Discussionmentioning

confidence: 99%

Metabolism of acetaminophen (paracetamol) in plants—two independent pathways result in the formation of a glutathione and a glucose conjugate

Huber¹,

Bartha²,

Harpaintner³

et al. 2009

Environ Sci Pollut Res

120

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“…As a consequence, metabolite identification is now performed at much an earlier phase of candidate selection, and with much a larger number of compounds. 1 Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) is particularly suitable for using MS 3 , it would be advantageous to monitor them quantitatively in the first pre-clinical studies, in order to ascertain their relevance in various in vivo systems. Accurate quantitation by LC/MS/MS can only be performed with the use of reference compounds.…”

Section: Introductionmentioning

confidence: 99%

Rapid screening and characterization of drug metabolites using a new quadrupole–linear ion trap mass spectrometer

2003

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The application of a new hybrid RF/DC quadrupole-linear ion trap mass spectrometer to support drug metabolism and pharmacokinetic studies is described. The instrument is based on a quadrupole ion path and is capable of conventional tandem mass spectrometry (MS/MS) as well as several high-sensitivity ion trap MS scans using the final quadrupole as a linear ion trap. Several pharmaceutical compounds, including trocade, remikiren and tolcapone, were used to evaluate the capabilities of the system with positive and negative turbo ionspray, using either information-dependent data acquisition (IDA) or targeted analysis for the screening, identification and quantification of metabolites. Owing to the MS/MS in-space configuration, quadrupole-like CID spectra with ion trap sensitivity can be obtained without the classical low mass cutoff of 3D ion traps. The system also has MS 3 capability which allows fragmentation cascades to be followed. The combination of constant neutral loss or precursor ion scan with the enhanced product ion scan was found to be very selective for identifying metabolites at the picogram level in very complex matrices. Owing to the very high cycle time and, depending on the mass range, up to eight different MS experiments could be performed simultaneously without compromising chromatographic performance. Targeted product ion analysis was found to be complementary to IDA, in particular for very low concentrations. Comparable sensitivity was found in enhanced product ion scan and selected reaction monitoring modes. The instrument is particularly suitable for both qualitative and quantitative analysis.

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“…Metabolites were identified based on charged molecular ions, mass accuracy, and their collision-induced dissociation fragmentation (Oliveira and Watson, 2000). Authentic standards, when available, were used to compare chromatographic retention times and fragmentation patterns.…”

mentioning

confidence: 99%

Disposition and Metabolism of Radiolabeled Casopitant in Humans

Pellegatti¹,

Bordini²,

Fizzotti³

et al. 2009

Drug Metab Dispos

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Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)-(GW679769)] is a novel neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. The disposition of [ 14 C]casopitant was determined in a single-sequence study in six healthy male subjects after single-dose 90-mg i.v. and 150-mg oral administration. Blood, urine, and feces were collected at frequent intervals after dosing. Plasma, urine, and fecal samples were analyzed by high-performance liquid chromatography/mass spectrometry coupled with off-line radiodetection for metabolite profiling. Moreover, urine was also analyzed with 1 H-NMR to further characterize metabolites. Plasma pharmacokinetic parameters for casopitant, a major metabolite (M13, coded as GSK525060), and total radioactivity were determined. Absorption of radioactivity after oral administration appeared to be nearly complete; elimination was principally via the feces both after oral and intravenous administration. Urinary elimination accounted for only <8% of total radioactivity. The main circulating metabolites were a hydroxylated derivative, M13 (coded as GSK525060), and, after oral administration, a deacetylated and oxidized metabolite, M12 (coded as GSK631832). In addition, many other metabolites were identified in plasma and excreta: the principal route of metabolism included multiple oxidations, loss of the N-acetyl group, modifications or loss of the piperazine group, and cleavage of the molecule. Casopitant was extensively metabolized, and only negligible amounts were excreted as unchanged compound. Some phase II metabolites were also observed, particularly in urine.Casopitant, also known as GW679769, is a novel, potent and selective orally available neurokinin-1 (NK-1) receptor antagonist, which has shown efficacy in the prevention of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (Arpornwirat et al., 2006;Chung et al., 2006;Rolski et al., 2006;Singla et al., 2006;Aziz et al., 2008;Grunberg et al., 2008;Herrstedt et al., 2008;Navari, 2008;Strausz et al., 2008). The site of action of NK-1 receptor antagonists for the prevention of emesis is believed to be the nucleus tractus solitarius, where vagal afferents from the gastrointestinal tract and inputs from the area postrema and other regions of the brain important in the control of emesis converge. For the prevention of nausea and vomiting, casopitant has been administered as a single dose or as part of an acute 3-day dosing regimen. Casopitant is administered in combination with a 5-HT3 receptor antagonist, such as ondansetron, and for the prevention of CINV, dexamethasone is also coadministered. Clinical studies have evaluated the safety and effectiveness of a single 50-mg oral dose of casopitant for postoperative nausea and vomiting and single (150 mg oral) or 3-day (90 mg i.v. or 150 mg oral on day 1, followed b...

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Liquid chromatography-mass spectrometry in the study of the metabolism of drugs and other xenobiotics

Cited by 69 publications

References 104 publications

Metabolism of acetaminophen (paracetamol) in plants—two independent pathways result in the formation of a glutathione and a glucose conjugate

Metabolism of acetaminophen (paracetamol) in plants—two independent pathways result in the formation of a glutathione and a glucose conjugate

Rapid screening and characterization of drug metabolites using a new quadrupole–linear ion trap mass spectrometer

Disposition and Metabolism of Radiolabeled Casopitant in Humans

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