Discovering drugs through biological transformation: Role of pharmacologically active metabolites in drug discovery

Journal of Medicinal Chemistry

Volumn 47, Issue 18, 2004, Pages 4339-4351

  Fura, Aberra ^a   Shu, Yue Zhong ^a   Zhu, Mingshe ^a   Hanson, Ronald L ^a   Roongta, Vikram ^a   Humphreys, W Griffith ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME;

BIOTRANSFORMATION; CELL FRACTIONATION; CELL LINE; DRUG ACTIVITY; DRUG DETERMINATION; DRUG DEVELOPMENT; DRUG DISCOVERY; DRUG METABOLISM; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; METABOLITE; NUCLEAR MAGNETIC RESONANCE; PROTEIN EXPRESSION; REVIEW; STRUCTURE ANALYSIS;

BIOTRANSFORMATION; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; PHARMACEUTICAL PREPARATIONS;

EID: 4143147349     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040066v     Document Type: Review

References (112)

1. Clader, J. W. The Discovery of Ezetimibe: A view from outside the receptor. J. Med. Chem. 2004, 47, 1-9.
2. Schmidt, B.; Schieffer, B. Angiotensin II AT1 receptor antagonist. Clinical implications of active metabolites. J. Med. Chem. 2003, 46, 2261-2270.
3. Garattini, S. Active drug metabolites: an overview of their relevance in clinical pharmacokinetics. Clin. Pharmacokinet. 1985, 10, 216-227.
4. Clissold, S. P. Paracetamol and phenacetin. Drugs. 1986, 32 (Suppl. 4), 46-59.
5. Flower, R. J.; Moncada, S.; Vane, J. R. Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. In The Pharmacological Basis of Therapeutics, 7th ed.; Gilman, A. G., Goodman, L. S., Rall, T. W., Murad, F., Eds.; Macmillan: New York, 1985; pp 674-715.
6. Baldessarini, R. J. Drugs and the treatment of psychiatric disorders. In The Pharmacological Basis of Therapeutics, 7th ed.; Gilman, A. G., Goodman, L. S., Rall, T. W., Murad, F., Eds.; Macmillan: New York, 1990; pp 383-435.
7. Mattila, M. J.; Paakkari, I. Variations among non-sedating antihistamines: are there real differences? Eur. J. Clin. Pharmacol. 1999, 55, 85-93.
8. Meeves, S. G.; Appajosyula, S. Efficacy and safety profile of fexofenadine HCl: a unique therapeutic option in H1-receptor antagonist treatment. J. Allergy Clin. Immunol. 2003, 112, S69-S77.
9. Murdoch, D.; Goa, K. L.; Keam, S. J. Desloratadine: an update of its efficacy in the management of allergic disorders. Drugs 2003, 63, 2051-2077.
10. Shet, M. S.; McPhaul, M.; Fisher, C. W.; Stallings, N. R.; Estabrook, R. W. Metabolism of the antiandrogenic drug (Flutamide) by human CYP1A2. Drug Metab. Dispos. 1997, 25, 1298-1303.
11. Anderson, R. J.; Kudlacek, P. E.; Clemens, D. L. Sulfation of minoxidil by multiple human cytosolic sulfotransferases. Chem.-Biol. Interact. 1998, 109, 53-67.
12. Fisher, M. B.; Paine, M. F.; Strelevitz, T. J.; Wrighton, S. A. The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab. Rev. 2001, 33, 273-279.
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.; Shipley, L. A. Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 2002, 182, 188-196.
14. Hastings, K. L.; El-Hage, J.; Jacobs, A.; Leighton, J.; Morse, D.; Osterberg, R. E.; Letter to the editor. Toxicol. Appl. Pharmacol. 2003, 190, 91-92.
15. White, R. E. High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery. Annu. Rev. Pharmacol. Toxicol. 2000, 40, 133-157.
16. Fura, A.; Lounsbury, H.; Yu, S.; Cai, X.; Yaeger, D.; Scannell, R.; Libertine, G. L.; Grewal, G.; Hussoin, S.; Killian, D. B.; Young, M.; Zuo, F.; Ellis, J.; Fisher, R.; Yeh, G. Structure-activity relationships and rate of glucuronidation of CMI-977 and its analogs. Pharm. Res. 1997, 14, (Suppl. 11), 552.
17. White, R. E. Short- and long-term projections about the use of drug metabolism in drug discovery and development. Drug. Metab. Dispos. 1998, 26, 1213-1216.
18. Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R., Jr.; Yumibe, N.; Clader, J. W.; Burnett, D. A. Discovery of 1-(4-Fluorophenyl)-(3R)-[3-(4- fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption. J. Med. Chem. 1998, 41, 973-980.
19. Yumibe, N.; Huie, K.; Chen, K. J.; Snow, M.; Clement, R. P.; Cayen, M. N. Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine: formation of descarboethoxyloaratadine by CYP3A4 and CYP2D6. Biochem. Pharmacol. 1995, 51, 165-172.
20. Norman, P.; Dihlmann, A.; Rabasseda, X. Desloratadine: A preclinical and clinical overview. Drugs Today. 2001, 37, 215-227.
21. Hibert, J.; Radwanski, E.; Weglein, R.; Lue, V.; Prerentesis, G.; Symchowicz, S. Pharmacokinetics and dose proportionality of loratadine. J. Clin. Pharmacol. 1987, 27, 694-698
22. Radwasnki, E.; Hilbert, J.; Symchowicz, S.; Zampaglione, N. Loratadine: Multiple dose pharmacokinetics. J. Clin. Pharmacol. 1987, 27, 530-533.
23. Osborne, R.; Thompson, P.; Joel, S.; Trew, D.; Patel, N.; Slevin, M. The analgesic activity of morphine 6-glucuronide. Br. J. Clin. Pharmacol. 1992, 34, 130-138.
24. Ritter, J. K. Roles of glucuronidation and UDP-glucuronosyl-transferases in xenobiotic bioactivation reactions. Chem.-Biol. Interact. 2000, 129, 171-193.
25. Portenoy, R. K.; Khan, E.; Layman, M.; Lapin, J.; Malkin, M. G.; Foley, K. M.; Thaler, H. T.; Cerbone, D. J.; Inturrisi, C. E. Chronic morphine therapy for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations. Neurology 1991, 41, 1527-1461.
26. 14C]levocetirizine, the R enantiomer of cetirizine, in healthy volunteers. Eur. J. Clin. Pharmacol. 2001, 57, 571-582.
27. Yun, C. H.; Okerholm, R. A.; Guengerich, F. P. Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation. Drug Metab. Dispos. 1993, 21, 403-409.
28. Woosley, R. L.; Chen, Y.; Freiman, J. P.; Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. JAMA, J. Am. Med. Assoc. 1993, 269, 1532-1536.
29. Crumb, W. J.; Wible, B.; Arnold, D. J.; Payne, J. P.; Brown, A. M. Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity. Mol. Pharmacol. 1995, 47, 181-190.
30. Honig, P. K.; Wortham, D. C.; Zamani, K.; Conner, D. P.; Mullin, J. C.; Cantilena, L. R. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA, J. Am. Med. Assoc. 1993, 269, 1513-1518.
31. Jensen, C. B.; Jollow, D. J. The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. Toxicol. Appl. Pharmacol. 1991, 111, 1-12.
32. Gonzalez, F. J. The molecular biology of cytochrome P450s. Pharmacol. Rev. 1988, 40, 243-288.
33. Van Heek, M.; France, C. F.; Compton, D. S.; McLeod, R. L.; Yumibe, N. P.; Alton, K. B.; Sybertz, E. J.; Davis, H. R., Jr. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH 58235, in the rat and rhesus monkey through identification of the active metabolites of SCH 48461. J. Pharmacol. Exp. Ther. 1997, 283, 157-163.
34. Khanna, A.; Humphreys, W. G.; Parker, R.; Hamann, L. Unpublished work.
35. Fura, A.; Vyas, V.; Harper, T.; Shyu, W. C.; Zhu, M.; Salvati, M.; Attar, R.; Humphreys, W. G. Drug Metab. Rev. 2002, 34 (Suppl. 1), 135.
36. Lim, H. K.; Stellingweif, S.; Sisenwine, S.; Chan, K. W. Rapid drug metabolite profiling using fast liquid chromatography, automated multiple-stage mass spectrometry and receptor-binding. J. Chromatogr., A 1999, 831, 227-241.
37. Soldner, A.; Spahn-Langguth, H.; Palm, D.; Mutschler, E. A. Radioreceptor assay for the analysis of AT1-receptor antagonists. Correlation with complementary LC data reveals a potential contribution of active metabolites. J. Pharm. Biomed. Anal. 1998, 17, 111-124.
38. Shu, Y.-Z.; Li, W. Y.; Leet, J. E.; Alberts, J.; Arora, V. K.; Yeola, S.; Philip, T.; Qian-Cutrone, J.; Zhao, N.; Santone, K.; Humphreys, W. G.; Dickinson, K. Biogram enabled evaluation of active metabolites: An exploratory approach for detecting and characterizing active/toxic drug metabolites. Drug Metab. Rev. 2002, 34 (Suppl. 1), 75.
39. Padmanabha, R.; Shu, Y.-Z.; Cook, L. S.; Donovan, M.; Veitch, J. A.; Lowe, S.; Huang, S.; Pirnik, D. M.; Manly, S. P. 1-Methoxy-agroclavine from Penicillium sp. WC75209, a novel inhibitor of the Lck tyrosine kinase. Bioorg. Med. Chem. Lett. 1998, 8, 569-574.
40. Luukkanen, L.; Mikkola, J.; Forsman, T.; Taavitsainen, P.; Taskinen, J.; Elovaara, E. Glucuronidation of 1-hydroxypyrene by human liver microsomes and human UDP-glucuronosyltransferases UGT1A6, UGT1A7, and UGT1A9: Development of a high-sensitivity glucuronidation assay for human tissue. Drug Metab. Dispos. 2001, 29, 1096-1101.
41. Gonzalez, F. J.; Kimura, S.; Tamura, S.; Gelboin, H. V. Expression of mammalian cytochrome P450 using baculovirus. Methods Enzymol. 1991, 206, 93-99.
42. Chen, L.; Muters, J. T. M.; Hardwick, J. P., Tamura, S.; Penman, B. W.; Gonzalez, F. J.; Crespi, C. L. Coexpression of cytochrome P4502A3 and human NADPH-P450 oxidoreductase in the baculovirus system. Drug Metab. Dispos. 1997, 25, 399-405.
43. Williams, J. A.; Hurst, S. I.; Bauman, J.; Jones, B. C.; Hyland, R.; Gibbs, J. P.; Obach, R. S.; Ball, S. E. Reaction phenotyping in drug discovery: moving forward with confidence? Curr. Drug Metab. 2003, 4, 527-534.
44. Rodrigues, A. D. Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem. Pharmacol. 1999, 57, 465-480.
45. Crespi, C. L.; Miller, V. P. The use of heterologously expressed drug metabolizing enzymes: state of the art and prospects for the future. Pharmacol Ther. 1999, 84, 121-131
46. Hiroshi, K.; Yoshihisa, O.; Yoshito, O.; Kyoji, U. Shigeru, N. Synthesis of acylglucuronides of drugs using immobilized dog liver microsomes octadecylsilica particles coated with phospholipid. Anal. Biochem. 2003, 317, 99-106.
47. Gillissen, R. A. H. J.; Meerman, J. H. N.; Mulder, G. J. Immobilization of solubilized UDP-glucuronosyltransferase from rat liver microsomes to Sepharose 4B. Biochem. Pharmacol. 1992, 43, 2661-2662.
48. Dulik, D. M.; Fenselau, C. Species-dependent glucuronidation of drugs by immobilized rabbit, rhesus monkey, and human UDP-glucuronosyl transferases. Drug Metab. Dispos. 1987, 15, 473-477.
49. Haumont, M.; Magdalou, J.; Ziegler, J. C.; Bidault, R.; Siest, J. P.; Siest, G. Immobilization of microsomes into alginate beads is a convenient method for producing glucuronides from drugs. Appl. Microbiol. Biotechnol. 1991, 35, 440-446.
50. Li, A. P.; Lu, C.; Brent, J. A.; Pham, C.; Fackett, A.; Ruegg, C. E.; Silber, P. M. Cryopreserved human hepatocytes: characterization of drug-metabolizing activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem.-Biol. Interact. 1999, 121, 17-35.
51. Ekins, S. Past, present and future applications of precision-cut liver slices for in vitro xenobiotic metabolism. Drug Metab. Rev. 1996, 28, 591-623.
52. Rushmore, T. H.; Reider, P. J.; Slaughter, D.; Assang, C.; Shou, M. Bioreactor systems in drug metabolism: synthesis of cytochrome P450-generated metabolites. Metab. Eng. 2000, 2, 115-125.
53. Zhu, M.; Moulin, F.; Aranibar, N.; Zhao, W.; Andrews, B.; Callahan, S.; Mitroka, J.; Klunk, L. Development of an immortalized cell-based P450 bioreactor system: rapid generation of human oxidative metabolites for structural elucidation by LC/NMR. Drug Metab. Rev. 2002, 34 (Suppl. 1), 205.
54. Stewart, J. S.; Bauman, A.; Barnes, H. J.; Johnson, D. A. Use of human CYP450-expressing bacteria for production of large quantities of drug metabolites. Drug Metab. Rev. 2002, 34 (Suppl. 1), 106.
55. Iwata, H.; Fujita, K.; Kushida, H.; Suzuki, A.; Konno, Y.; Nakamura, K.; Fujino, A.; Kamataki, T. High catalytic activity of human cytochrome P450 co-expressed with human NADPH-cytochrome P450 reeducates in Escherichia coli. Biochem. Pharmacol. 1998, 55, 1315-1325.
56. Pfeifer, A. M. A.; Cole, K. E.; Smoot, D. T.; Weston, A.; Groopman, J. D.; Shields, P. G.; Vignaud, J.; Juillerat, M.; Lipsky, M. M.; Trump, B. F.; Lechner, J. F.; Harris, C. C. Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5123-5127.
57. Harris, C. C.; Gelboin, H. V.; Gonzalez, F.; Pfeifer, A. M. A. Immortalized human cell line containing exogenous cytochrome P450. Biotechnol. Adv. 1995, 13, 275.
58. Rosazza, J. P.; Smith, R. V. Microbial models for drug metabolism. Adv. Appl. Microbiol. 1979, 25, 169-208.
59. Zhang, D.; Yang, Y.; Leakey, J. E. A.; Cerniglia, C. E. Phase I and Phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbiol. Lett. 1996, 138, 221-226.
60. Dhar, K.; Dharand, A.; Rosazza, J. P. N. Glutathione S-transferase from Streptomyces griseus. Appl. Environ. Microbiol. 2003, 69, 707-710.
61. Kim, D.; Kim, H.; Kobashi, K. Purification and characterization of novel sulfotransferase obtained from Klebsiella K-36, an intestinal bacterium of rat. J. Biochem. 1992, 112, 456-460.
62. Smith, R. V.; Rosazza, J. P. Microbial models of mammalian metabolism. Aromatic hydroxylation. Arch. Biochem. Biophys. 1974, 161, 551-558.
63. Sariaslani, F. S.; Kunz, D. A. Induction of cytochrome P-450 in Streptomyces griseus by soybean flour. Biochem. Biophys. Res. Commun. 1986, 141, 405-410.
64. Hanson, R. L.; Matson, J. A.; Brzozowski, D. B.; LaPorte, T. L.; Springer, D. M.; Patel, R. N. Hydroxylation of mutilin by Streptomyces griseus and Cunninghamella echinulata. Org. Process Res. Dev. 2002, 6, 482-487.
65. Smith, R. V.; Rosazza, J. P. Microbial models of mammalian metabolism. J. Pharm. Sci. 1975, 64, 1737-1759.
66. Smith, R. V.; Rosazza, J. P. Microbial models of mammalian metabolism. J. Nat. Prod. 1983, 46, 79-91.
67. Abourashed, E. A.; Clark, A. M.; Hufford, C. D. Microbial models of mammalian metabolism of xenobiotics: An updated review. Curr. Med. Chem. 1999, 6, 359-374.
68. Azerad, R. Microbial models for drug metabolism. Adv. Biochem. Eng. Biotechnol. 1999, 63, 169-218.
69. Serizawa, N. Biocatalytic production of pravastatin, an anticholesterol drug. In Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New York, 2000; pp 703-711.
70. Zhang, D.; Evans, F. E.; Freeman, J. P.; Duhart, B.; Cerniglia, C. E. Biotransformation of amitryptyline by Cunninghamella elegans. Drug Metab. Dispos. 1995, 23, 1417-1425.
71. Watt, A. P.; Mortishire-Smith, R. J.; Gerhard, U.; Thomas, S. R. Metabolite identification in drug discovery. Curr. Opin. Drug Discovery Dev. 2003, 6, 57-65.
72. Kostiainen, R.; Kotiaho, T.; Kuuranne, T.; Auriola, S. Liquid chromatography/atmospheric pressure ionization-mass spectrometry in drug metabolism studies. J. Mass Spectrom. 2003, 38, 357-372.
73. Clarke, N. J.; Rindgen, D.; Korfmacher, W. A.; Cox, K. A. Systematic LC/MS metabolite identification in drug discovery. Anal. Chem. 2001, 73, 430A-439A.
74. Papac, D. I.; Shahrokh, Z. Mass spectrometry innovations in drug discovery and development. Pharm. Rev. 2001, 18, 131-145.
75. Fernández-Metzler, C. L.; Owens, K. G.; Baillie, T. A.; King, R. C. Rapid liquid chromatography with tandem mass spectrometry-based screening procedures for studies on the biotransformation of drug candidates. Drug Metab. Dispos. 1999, 27, 32-40.
76. Korfmacher, W. A.; Cox, K. A.; Bryant, M. S.; Veals, J.; Watkins, K. R.; In, C. C. HPLC-API/MS/MS: a powerful tool for integrating drug metabolism into the drug discovery process. Drug Discovery Today 1997, 2, 532-537.
77. Bruins, A. P. Atmospheric pressure ionization mass spectrometry: application in pharmacy, biochemistry and general chemistry. Trends Anal. Chem. 1994, 13, 81-90.
78. Brewer, E.; Henion, J. Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies. J. Pharm. Sci. 1998, 87, 395-402.
79. Keski-Hynnilä, H.; Kurkela, M.; Elovaara, E.; Antonio, L.; Magdalou, J.; Luukkanen, L.; Taskinen, J.; Kostiainen, R. Comparison of electrospray, atmospheric pressure chemical ionization, and atmospheric pressure photoionization in the identification of apomorphine, dobutamine, and entacapone phase II metabolites in biological samples. Anal. Chem. 2002, 74, 3449-3457.
80. Williams, A. Applications of computer software for the interpretation and management of mass spectrometry data in pharmaceutical science. Curr. Top. Med. Chem. 2002, 2, 99-107.
81. Ramanathan, R.; McKenzie, D. L.; Tugnait, M.; Siebenaler, K. Application of semi-automated metabolite identification software in the drug discovery process for rapid identification of metabolites and the cytochrome P450 enzymes responsible for their formation. J. Pharm. Biomed. Anal. 2002, 28, 945-951.
82. Jemal, M.; Teitz, D.; Ouyang, Z.; Khan, S. Comparison of plasma sample purification by manual liquid-liquid extraction, automated 96-well liquid-liquid extraction and automated 96-well solid-phase extraction for analysis by high-performance liquid chromatography with tandem mass spectrometry. J. Chromatogr. Biomed. Sci. Appl. 1999, 732, 501-508.
83. McLafferty, F. W.; Turecek, F. Interpretation of Mass Spectra; University Science Books: Mill Valley, CA, 1993; pp 103-114.
84. Jemal, M.; Ouyang, Z.; Zhao, W.; Zhu, M.; Wu, W. W. A strategy for metabolite identification using triple-quadrupole mass spectrometry with enhanced resolution and accurate mass capability. Rapid Commun. Mass Spectrom. 2003, 17, 2732-2740.
85. Hopfgartner, G.; Cherushevich, I. V.; Covey, T.; Plomley, J. B.; Boner, R. Exact mass measurement of product ions for the structural elucidation of drug metabolism with a tandem quadrupole orthogonal-acceleration time of flight mass spectrometer. J. Am. Soc. Mass Spectrom. 1999, 10, 1305-1314.
86. Hopfgartner, G.; Husser, C.; Zell, M. Rapid screening and characterization of drug metabolites using a new quadrupole-linear ion trap mass spectrometer. J. Mass Spectrom. 2003, 38, 138-150.
87. Xia, Y.; Miller, J. D.; Bakhtiar, R.; Franklin, R. B.; Liu, D. Q. Use of a quadrupole linear ion trap mass spectrometer in metabolite identification and bioanalysis. Rapid Commun. Mass Spectrom. 2003, 17, 1137-1145.
88. Tiller, P. R.; Land, A. P.; Jardine, I.; Murphy, D. M.; Sozio, R.; Ayrton, A.; Schaefer, W. H. Application of liquid chromatography-mass spectrometry analyses to the characterization of novel glyburide metabolites formed in vitro. J. Chromatogr., A 1998, 794, 15-25.
89. Liu, D. Q.; Xia., Y. Q.; Bakhtiar, R. Use of liquid chromatography/ion trap mass spectrometry/triple quadrupole mass spectrometry system for metabolite identification. Rapid. Commun. Mass Spectrom. 2002, 16, 1330-1336.
90. Dear, G. J.; Ayrton, J.; Plumb, R.; Fraser, I. J. The rapid identification of drug metabolites using capillary liquid chromatography coupled to an ion trap mass spectrometer. Rapid Commun. Mass Spectrom. 1999, 13, 456-463.
91. Sundstorm, L.; Hedeland, M.; Bondesson, U.; Andren, P. E. Identification of glucuronide conjugates of ketobemidone and its phase I metabolites in human urine utilizing accurate mass and tandem time-of-flight mass spectrometry. J. Mass Spectrom. 2002, 37, 414-420.
92. Martin, G.; Zektzer, A. Two-Dimensional NMR Methods for Establishing Molecular Connectivity; VCH: New York, 1988.
93. Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR Experiments; Wiley-VCH: New York, 1998.
94. Holzgrabe, U. NMR Spectroscopy in Drug Development and Analysis; Wiley-VCH: New York, 1999.
95. Fitch, W. L.; Detre, G.; Holmes, C. P.; Shoolery, J. N.; Keifer, P. A. High-Resolution H-1-NMR in solid-phase organic-synthesis. J. Org. Chem. 1994, 59, 7955-7956.
96. Bruker Biospin GmbH: Bruker BioSpin announces novel capillary LC-NMR system. Press release (March 2002).
97. Bruker Biospin GmbH: Bruker BioSpin introduces the CryoFlowProbe, the world's first cryogenic flow-injection NMR probe. Press release (March 2002).
98. Schlotterbeck, G.; Ross, A.; Hochstrasser, R.; Senn, H.; Kuhn, T.; Marek, D.; Schett, O.; High-resolution capillary tube NMR. A miniaturized 5 mL high-sensitivity TXI probe for mass-limited samples, off-line LC NMR, and HT NMR. Anal. Chem. 2002, 74, 4464-4471.
99. 1H NMR spectroscopy using a 1 mm microlitre probe. Analyst 2002, 127, 582-584.
100. NMR Probes; Varian Inc., Palo Alto, CA, 2001.
101. 13C NMR spectroscopy of urine for metabonomic studies. Anal. Chem. 2002, 74, 4588-4593.
102. 1H NMR spectroscopy for drug metabolite detection and characterization: the identification of paracetamol metabolites in urine and bile. NMR Biomed. 1994, 7, 295-303.
103. Smallcombe, S. H.; Patt, S. L.; Keifer, P. A. Wet solvent suppression and its applications to LC NMR and high-resolution NMR spectroscopy. J. Magn. Reson. A 1995, 117, 295-303.
104. Spraul, M.; Hofmann, M.; Dvortsak, P.; Nicholson, J. K.; Wilson, I. D. High-performance liquid-chromatography coupled to high-field proton nuclear magnetic resonance spectroscopy: application to the urinary metabolites of ibuprofen. Anal. Chem. 1993, 65, 327-330.
105. Albert, K. Online use of NMR detection in separation chemistry. J. Chromatogr., A 1995, 703, 123-147.
106. Lindon, J. C.; Nicholson, J. K.; Wilson, I. D. The development and application of coupled HPLC-NMR spectroscopy. Adv. Chromatogr. 1996, 36, 315-382.
107. Shockcor, J. P.; Unger, S. H.; Wilson, I. D.; Foxall, P. J. D.; Nicholson, J. K.; Lindon, J. C. Combined hyphenation of HPLC, NMR spectroscopy and ion trap mass spectrometry (LC-NMR-MS) with application to the detection and characterization of xenobiotic and endogenous metabolites in human urine. Anal. Chem. 1996, 68, 4431-4435.
108. Pullen, F. S.; Swanson, A. G.; Newman, M. J.; Richards, D. S. On line LC/NMR/MSs: a powerful spectroscopic tool for the analysis of mixtures of pharmaceutical interest. Rapid Commun. Mass Spectrom. 1995, 9, 1003-1006.
109. Chen, H.; Shockcor, J.; Chen, W.; Espina, R.; Gan, L.-S.; Mutlib, A. E. Delineating novel metabolic pathways of DPC 963, a non-nucleoside reverse transcriptase inhibitor, in rats: Characterization of glutathione conjugates of postulated oxirene and benzoquinone imine intermediates by LC/MS and LC/NMR. Chem. Res. Toxicol. 2002, 15, 388-399.
110. Griffiths, L.; Horton, R. Optimization of LC-NMR. III. Increased signal-to-noise ratio through column trapping. Magn. Reson. Chem. 1998, 36, 104-109.
111. Bruker Biospin GmbH: SPE boosts LC-NMR performance. Press release (March 2001)
112. Vassiliki, E.; Godejohann, M.; van Beek, T. A.; Gerothanassis, I. P.; Vervoort, J. LC-UV-Solid-Phase Extraction-NMR-MS Combined with a Cryogenic Flow Probe and Its Application to the Identification of Compounds Present in Greek Oregano. Anal. Chem. 2003, 75, 6288-6294.