Rapid detection and characterization of in vitro and urinary N-acetyl-L-cysteine conjugates using quadrupole-linear ion trap mass spectrometry and polarity switching

Chemical Research in Toxicology

Volumn 22, Issue 7, 2009, Pages 1246-1255

  Jian, Wenying ^a,b   Yao, Ming ^a   Zhang, Duxi ^a   Zhu, Mingshe ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b Pharmaceutical Research and Development   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCYSTEINE DERIVATIVE; CLOZAPINE; DICLOFENAC; GLUTATHIONE; PARACETAMOL;

ARTICLE; CONTROLLED STUDY; DRUG CONJUGATION; HUMAN; HUMAN EXPERIMENT; ION TRAP MASS SPECTROMETRY; LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MASS SPECTROMETRY; NONHUMAN; NORMAL HUMAN; RAT; SENSITIVITY ANALYSIS; URINALYSIS;

ACETAMINOPHEN; ACETYLCYSTEINE; ANALGESICS, NON-NARCOTIC; ANIMALS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CLOZAPINE; DICLOFENAC; GLUTATHIONE; HUMANS; MICROSOMES, LIVER; RATS; TANDEM MASS SPECTROMETRY;

EID: 67651007115     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx900035j     Document Type: Article

References (47)

1. Kalgutkar, A. S., Gardner, I., Obach, R. S., Shaffer, C. L., Callegari, E., Henne, K. R., Mutlib, A. E., Dalvie, D. K., Lee, J. S., Nakai, Y., O'Donnell, J. P., Boer, J., and Harriman, S. P. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 6, 161-225.
2. Nelson, S. D. (2001) Structure toxicity relationships - How useful are they in predicting toxicities of new drugs. In Biological Reactive Intermediates VI: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Enviornmental Diseases (Dansette, P. M., Snyder, R., Delaforge, M., Goibson, G. G., Greom, H., Jollow, D. J., Monks, T. J., and Sipes, I. G., Eds.) pp 33-44, Kluwer Academic/Plenum Publishers, New York.
3. Guengerich, F. P. (2005) Generation of reactive intermediates. J. Biochem. Mol. Toxicol. 19, 173-174.
4. Blair, I. A. (2006) Endogenous glutathione adducts. Curr. Drug Metab. 7, 853-872.
5. Ma, S., and Zhu, M. (2009) Recent advances in applications of liquid chromatography-tandem mass spectrometry to the analysis of reactive drug metabolites. Chem.-Biol. Interact. 179, 25-37.
6. Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., and Baillie, T. A. (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17, 3-16.
7. Uetrecht, J. (2003) Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discovery Today 8, 832-837.
8. Williams, D. P., Kitteringham, N. R., Naisbitt, D. J., Pirmohamed, M., Smith, D. A., and Park, B. K. (2002) Are chemically reactive metabolites responsible for adverse reactions to drugs? Curr. Drug Metab. 3, 351-366.
9. Evans, D. C., and Baillie, T. A. (2005) Minimizing the potential for metabolic activation as an integral part of drug design. Curr. Opin. Drug Discovery Dev. 8, 44-50.
10. Gopaul, S. V., Farrell, K., and Abbott, F. S. (2000) Identification and characterization of N-acetylcysteine conjugates of valproic acid in humans and animals. Drug Metab. Dispos. 28, 823-832.
11. Thompson, C. D., Barthen, M. T., Hopper, D.W., Miller, T. A., Quigg, M., Hudspeth, C., Montouris, G., Marsh, L., Perhach, J. L., Sofia, R. D., and Macdonald, T. L. (1999) Quantification in patient urine samples of felbamate and three metabolites: Acid carbamate and two mercapturic acids. Epilepsia 40, 769-776.
12. U.S. FDA (2008) Guidance for Industry: Safety Testing of Drug Metabolites; www.fda.gov/CDER/GUIDANCE/6897fnl.pdf.
13. Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. G., and Shipley, L. A. (2002) Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 182, 188-196.
14. Smith, D. A., and Obach, R. S. (2006) Metabolites and safety: What are the concerns, and how should we address them? Chem. Res. Toxicol. 19, 1570-1579.
15. Smith, D. A., and Obach, R. S. (2005) Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab. Dispos. 33, 1409-1417.
16. Leclercq, L., Cuyckens, F., Mannens, G. S., de Vries, R., Timmerman, P., and Evans, D. C. (2009) Which human metabolites have we MIST? Retrospective analysis, practical aspects, and perspectives for metabolite identification and quantification in pharmaceutical development. Chem. Res. Toxicol. 22, 280-293.
17. Wagner, S., Scholz, K., Donegan, M., Burton, L., Wingate, J., and Volkel, W. (2006) Metabonomics and biomarker discovery: LC-MS metabolic profiling and constant neutral loss scanning combined with multivariate data analysis for mercapturic acid analysis. Anal. Chem. 78, 1296-1305.
18. Boettcher, M. I., Schettgen, T., Kutting, B., Pischetsrieder, M., and Angerer, J. (2005) Mercapturic acids of acrylamide and glycidamide as biomarkers of the internal exposure to acrylamide in the general population. Mutat. Res. 580, 167-176.
19. Prakash, C., Sharma, R., Gleave, M., and Nedderman, A. (2008) In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery. Curr. Drug Metab. 9, 952-964.
20. Yan, Z., and Caldwell, G. W. (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal. Chem. 76, 6835-6847.
21. Dieckhaus, C. M., Fernandez-Metzler, C. L., King, R., Krolikowski, P. H., and Baillie, T. A. (2005) Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem. Res. Toxicol. 18, 630-638.
22. Wen, B., Ma, L., Nelson, S. D., and Zhu, M. (2008) High-throughput screening and characterization of reactive metabolites using polarity switching of hybrid triple quadrupole linear ion trap mass spectrometry. Anal. Chem. 80, 1788-1799.
23. Wen, B., and Fitch, W. L. (2009) Screening and characterization of reactive metabolites using glutathione ethyl ester in combination with Q-trap mass spectrometry. J. Mass Spectrom. 44, 90-100.
24. Soglia, J. R., Harriman, S. P., Zhao, S., Barberia, J., Cole, M. J., Boyd, J. G., and Contillo, L. G. (2004) The development of a higher throughput reactive intermediate screening assay incorporating microbore liquid chromatography-micro-electrospray ionization-tandem mass spectrometry and glutathione ethyl ester as an in vitro conjugating agent. J. Pharm. Biomed. Anal. 36, 105-116.
25. Zheng, J., Ma, L., Xin, B., Olah, T., Humphreys, W. G., and Zhu, M. (2007) Screening and identification of GSH-trapped reactive metabolites using hybrid triple quadruple linear ion trap mass spectrometry. Chem. Res. Toxicol. 20, 757-766.
26. Zhu, M., Ma, L., Zhang, H., and Humphreys, W. G. (2007) Detection and structural characterization of glutathione-trapped reactive metabolites using liquid chromatography-high-resolution mass spectrometry and mass defect filtering. Anal. Chem. 79, 8333-8341.
27. Zhang, H., and Yang, Y. (2008) An algorithm for thorough background subtraction from high-resolution LC/MS data: application for detection of glutathione-trapped reactive metabolites. J. Mass Spectrom. 1181-1190.
28. Zhang, H., Ma, L., He, K., and Zhu, M. (2008) An algorithm for thorough background subtraction from high-resolution LC/MS data: application to the detection of troglitazone metabolites in rat plasma, bile, and urine. J. Mass Spectrom. 43, 1191-1200.
29. Lim, H. K., Chen, J., Cook, K., Sensenhauser, C., Silva, J., and Evans, D. C. (2008) A generic method to detect electrophilic intermediates using isotopic pattern triggered data-dependent high-resolution accurate mass spectrometry. Rapid Commun. Mass Spectrom. 22, 1295-1311.
30. Ma, L., Wen, B., Ruan, Q., and Zhu, M. (2008) Rapid screening of glutathione-trapped reactive metabolites by linear ion trap mass spectrometry with isotope pattern-dependent scanning and postacquisition data mining. Chem. Res. Toxicol. 21, 1477-1483.
31. Yan, Z., Caldwell, G. W., and Maher, N. (2008) Unbiased high-throughput screening of reactive metabolites on the linear ion trap mass spectrometer using polarity switch and mass tag triggered data-dependent acquisition. Anal. Chem. 80, 6410-6422.
32. Ma, S., and Subramanian, R. (2006) Detecting and characterizing reactive metabolites by liquid chromatography/tandem mass spectrometry. J. Mass Spectrom. 41, 1121-1139.
33. Scholz, K., Dekant, W., Volkel, W., and Pahler, A. (2005) Rapid detection and identification of N-acetyl-L-cysteine thioethers using constant neutral loss and theoretical multiple reaction monitoring combined with enhanced product-ion scans on a linear ion trap mass spectrometer. J. Am. Soc. Mass Spectrom. 16, 1976-1984.
34. Wagner, S., Scholz, K., Sieber, M., Kellert, M., and Voelkel, W. (2007) Tools in metabonomics: an integrated validation approach for LCMS metabolic profiling of mercapturic acids in human urine. Anal. Chem. 79, 2918-2926.
35. Hager, J. W., and Le Blanc, J. C. (2003) High-performance liquid chromatography-tandem mass spectrometry with a new quadrupole/linear ion trap instrument. J. Chromatogr. 1020, 3-9.
36. Hopfgartner, G., Varesio, E., Tschappat, V., Grivet, C., Bourgogne, E., and Leuthold, L. A. (2004) Triple quadrupole linear ion trap mass spectrometer for the analysis of small molecules and macromolecules. J. Mass Spectrom. 39, 845-855.
37. King, R., and Fernandez-Metzler, C. (2006) The use of Qtrap technology in drug metabolism. Curr. Drug Metab. 7, 541-545.
38. Le Blanc, J. C., Hager, J. W., Ilisiu, A. M., Hunter, C., Zhong, F., and Chu, I. (2003) Unique scanning capabilities of a new hybrid linear ion trap mass spectrometer (Q TRAP) used for high sensitivity proteomics applications. Proteomics 3, 859-869.
39. Fitch, W. L., He, L., Tu, Y. P., and Alexandrova, L. (2007) Application of polarity switching in the identification of the metabolites of RO9237. Rapid Commun. Mass Spectrom. 21, 1661-1668.
40. Pirmohamed, M., Williams, D., Madden, S., Templeton, E., and Park, B. K. (1995) Metabolism and bioactivation of clozapine by human liver in vitro. J. Pharmacol. Exp. Ther. 272, 984-990.
41. Yu, L. J., Chen, Y., Deninno, M. P., O'Connell, T. N., and Hop, C. E. (2005) Identification of a novel glutathione adduct of diclofenac, 4′-hydroxy-2′-glutathion-deschloro-diclofenac, upon incubation with human liver microsomes. Drug Metab. Dispos. 33, 484-488.
42. Dahlin, D. C., Miwa, G. T., Lu, A. Y., and Nelson, S. D. (1984) N-Acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. U.S.A. 81, 1327-1331.
43. Hinson, J. A., Pohl, L. R., Monks, T. J., Gillette, J. R., and Guengerich, F. P. (1980) 3-Hydroxyacetaminophen: a microsomal metabolite of acetaminophen. Evidence against an epoxide as the reactive metabolite of acetaminophen. Drug Metab. Dispos. 8, 289-294.
44. Andrews, R. S., Bond, C. C., Burnett, J., Saunders, A., and Watson, K. (1976) Isolation and identification of paracetamol metabolites. J. Int. Med. Res. 4, 34-39.
45. Godejohann, M., Tseng, L. H., Braumann, U., Fuchser, J., and Spraul, M. (2004) Characterization of a paracetamol metabolite using on-line LC-SPE-NMR-MS and a cryogenic NMR probe. J. Chromatogr. 1058, 191-196.
46. Ladds, G., Wilson, K., and Burnett, D. (1987) Automated liquid chromatographic method for the determination of paracetamol and six metabolites in human urine. J. Chromatogr. 414, 355-364.
47. Chen, W., Shockcor, J. P., Tonge, R., Hunter, A., Gartner, C., and Nelson, S. D. (1999) Protein and nonprotein cysteinyl thiol modification by N-acetyl-p-benzoquinone imine via a novel ipso adduct. Biochemistry 38, 8159-8166.