Abstract
Identification and elucidation of the structures of metabolites play major roles in drug discovery and in the development of pharmaceutical compounds. These studies are also important in toxicology or doping control with either pharmaceuticals or illicit drugs. This review focuses on: new analytical strategies used to identify potential metabolites in biological matrices with and without radiolabeled drugs; use of software for metabolite profiling; interpretation of product spectra; profiling of reactive metabolites; development of new approaches for generation of metabolites; and detection of metabolites with increased sensitivity and simplicity. Most of the new strategies involve mass spectrometry (MS) combined with liquid chromatography (LC).
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Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA (2002) Toxicol Appl Pharmacol 182:188–196
Smith DA, Obach RS (2005) Drug Metab Dispos 33:1409–1417
Smith DA, Obach RS (2006) Chem Res Toxicol 19:1570–1579
Maurer HH (2004) Clin Chem Lab Med 42:1310–1324
Kostiainen R, Kotiaho T, Kuuranne T, Auriola S (2003) J Mass Spectrom 38:357–372
Korfmacher WA (ed) (2005) Using mass spectrometry for drug metabolism studies. CRC Press Boca Raton, Florida
Hopfgartner G (2006) The encyclopedia of mass spectrometry 8: hyphenated methods, Elsevier, edited by W.M.A. Niessen
Egnash LA, Ramanathan R (2002) J Pharm Biomed Anal 27:271–284
Nedderman AN, Savage ME, White KL, Walker DK (2004) J Pharm Biomed Anal 34:607–617
Schultz GA, Alexander JN (1998) J Microcolumn Sep 10:431–437
Onisko BC (2002) J Am Soc Mass Spectrom 13:82–84
Andrews CL, Li F, Yang E, Yu CP, Vouros P (2006) J Mass Spectrom 41:43–49
Nassar AE (2003) J Chromatogr Sci 41:398–404
Nassar AE, Bjorge SM, Lee DY (2003) Anal Chem 75:785–790
Chando TJ, Everett DW, Kahle AD, Starrett AM, Vachharajani N, Shyu WC, Kripalani KJ, Barbhaiya RH (1998) Drug Metab Dispos 26:408–417
Zhu M, Zhao W, Vazquez N, Mitroka JG (2005) J Pharm Biomed Anal 39:233–245
Boernsen KO, Floeckher JM, Bruin GJ (2000) Anal Chem 72:3956–3959
Kiffe M, Jehle A, Ruembeli R (2003) Anal Chem 75:723–730
Dear GJ, Patel N, Kelly PJ, Webber L, Yung M (2006) J Chromatogr B 844:96–103
Borts DJ, Cook ST, Bowers GD, O’Mara MJ, Quinn KE (2004) Proceedings of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics Nashville, Tennessee, May 23–27, 2004
Staack RF, Varesio E, Hopfgartner G (2005) Rapid Commun Mass Spectrom 19:618–626
Chen Y, Yu LJ, Hop CECA (2004) Proceedings of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics Nashville, Tennessee, May 23–27, 2004
Yu LJ, Chen Y, Deninno MP, O’Connell TN, Hop CE (2005) Drug Metab Dispos 33:484–488
Hopfgartner G, Staack RF, Varesio E (2004) Proceedings of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics Nashville, Tennessee, May 23–27, 2004
Anari MR, Sanchez RI, Bakhtiar R, Franklin RB, Baillie TA (2004) Anal Chem 76:823–832
Anari MR, Baillie TA (2005) Drug Discov Today 10:711–717
Hakala KS, Kostiainen R, Ketola RA (2006) Rapid Commun Mass Spectrom 20:2081–2090
Maurer HH, Pfleger K, Weber AA (2007) Mass spectral and GC data of drugs, poisons, pesticides, pollutants and their metabolites, 3rd edn. Wiley–VCH, Weinheim
Gergov M, Weinmann W, Meriluoto J, Uusitalo J, Ojanpera I (2004) Rapid Commun Mass Spectrom 18:1039–1046
Milman BL (2005) Rapid Commun Mass Spectrom 19:2833–2839
Josephs JL, Sanders M (2004) Rapid Commun Mass Spectrom 18:743–759
Mueller CA, Weinmann W, Dresen S, Schreiber A, Gergov M (2005) Rapid Commun Mass Spectrom 19:1332–1338
Jansen R, Lachatre G, Marquet P (2005) Clin Biochem 38:362–372
Sauvage FL, Saint-Marcoux F, Duretz B, Deporte D, Lachatre G, Marquet P (2006) Clin Chem 52:1735–1742
Sleno L, Volmer DA, Marshall AG (2005) J Am Soc Mass Spectrom 16:183–198
Kerns EH, Rourick RA, Volk KJ, Lee MS (1997) J Chromatogr B 698:133–145
Tozuka Z, Kaneko H, Shiraga T, Mitani Y, Beppu M, Terashita S, Kawamura A, Kagayama A (2003) J Mass Spectrom 38:793–808
Hopfgartner G, Vetter W, Meister W, Ramuz H (1996) Journal of Mass Spectrometry 31:69–76
Sweeney DL (2003) Anal Chem 75:5362–5373
Hill AW, Mortishire-Smith RJ (2005) Rapid Commun Mass Spectrom 19:3111–3118
Liu DQ, Hop CE (2005) J Pharm Biomed Anal 37:1–18
Lazarou J, Pomeranz BH, Corey PN (1998) Jama 279:1200–1205
Walgren JL, Mitchell MD, Thompson DC (2005) Crit Rev Toxicol 35:325–361
Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y, O’Donnell JP, Boer J, Harriman SP (2005) Curr Drug Metab 6:161–225
Liebler DC, Guengerich FP (2005) Nat Rev Drug Discov 4:410–420
Uetrecht J (2007) Annu Rev Pharmacol Toxicol 47:513–539
Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP (2005) Annu Rev Pharmacol Toxicol 45:177–202
Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA (2004) Chem Res Toxicol 17:3–16
Ma S, Subramanian R (2006) J Mass Spectrom 41:1121–1139
Chen Y, Monshouwer M, Fitch WL (2007) Pharm Res 24:248–257
Caldwell GW, Yan Z (2006) Curr Opin Drug Discov Dev 9:47–60
Uetrecht J (2003) Drug Discov Today 8:832–837
Brandon EF, Raap CD, Meijerman I, Beijnen JH, Schellens JH (2003) Toxicol Appl Pharmacol 189:233–246
Itakura K, Furuhata A, Shibata N, Kobayashi M, Uchida K (2003) Biochem Biophys Res Commun 308:452–457
Henderson AP, Bleasdale C, Clegg W, Golding BT (2004) Chem Res Toxicol 17:378–382
Gorrod JW, Aislaitner G (1994) Eur J Drug Metab Pharmacokinet 19:209–217
Gorrod JW, Whittlesea CM, Lam SP (1991) Adv Exp Med Biol 283:657–664
Thompson DC, Perera K, London R (1995) Chem Res Toxicol 8:55–60
Hartman NR, Cysyk RL, Bruneau-Wack C, Thenot JP, Parker RJ, Strong JM (2002) Chem Biol Interact 142:43–55
Baillie TA, Davis MR (1993) Biol Mass Spectrom 22:319–325
Mutlib A, Lam W, Atherton J, Chen H, Galatsis P, Stolle W (2005) Rapid Commun Mass Spectrom 19:3482–3492
Castro-Perez J, Plumb R, Liang L, Yang E (2005) Rapid Commun Mass Spectrom 19:798–804
Grillo MP, Hua F, Knutson CG, Ware JA, Li C (2003) Chem Res Toxicol 16:1410–1417
Dieckhaus CM, Fernandez-Metzler CL, King R, Krolikowski PH, Baillie TA (2005) Chem Res Toxicol 18:630–638
Yan Z, Maher N, Torres R, Caldwell GW, Huebert N (2005) Rapid Commun Mass Spectrom 19:3322–3330
Yan Z, Caldwell GW (2004) Anal Chem 76:6835–6847
Mutlib A, Shockcor J, Chen SY, Espina R, Lin J, Graciani N, Prakash S, Gan LS (2001) Drug Metab Dispos 29:1296–1306
Soglia JR, Harriman SP, Zhao S, Barberia J, Cole MJ, Boyd JG, Contillo LG (2004) J Pharm Biomed Anal 36:105–116
Gan J, Harper TW, Hsueh MM, Qu Q, Humphreys WG (2005) Chem Res Toxicol 18:896–903
Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu CP, Vouros P, Yang E (2005) Chem Res Toxicol 18:1537–1544
Meneses-Lorente G, Sakatis MZ, Schulz-Utermoehl T, De NC, Watt AP (2006) Anal Biochem 351:266–272
Reichardt P, Schreiber A, Wichmann G, Metzner G, Efer J, Raabe F (2003) Environ Toxicol 18:29–36
Wang J, Davis M, Li F, Azam F, Scatina J, Talaat R (2004) Chem Res Toxicol 17:1206–1216
Bailey MJ, Dickinson RG (2003) Chem Biol Interact 145:117–137
Boelsterli UA (2002) Curr Drug Metab 3:439–450
Fred C, Haglund J, Alsberg T, Rydberg P, Minten J, Tornqvist M (2004) J Sep Sci 27:607–612
Haglund J, Silvari V, Esmans E, Tornqvist M (2006) J Chromatogr A 1119:246–250
Girelli AM, Mattei E (2005) J Chromatogr B 819:3–16
Markoglou N, Hsuesh R, Wainer IW (2004) J Chromatogr B 804:295–302
Kim HS, Wainer IW (2005) J Chromatogr B 823:158–166
Sakai-Kato K, Kato M, Toyo’oka T (2002) Anal Biochem 308:278–284
Sakai-Kato K, Kato M, Toyo’oka T (2004) J Chromatogr A 1051:261–266
Kim HS, Wainer IW (2006) Anal Chem 78:7071–7077
Johnson BM, Nikolic D, van Breemen RB (2002) Mass Spectrom Rev 21:76–86
Benetton S, Kameoka J, Tan A, Wachs T, Craighead H, Henion JD (2003) Anal Chem 75:6430–6436
Karst U (2004) Angew Chem 43:2476–2478
van Leeuwen SM, Blankert B, Kauffmann JM, Karst U (2005) Anal Bioanal Chem 382:742–750
Lohmann W, Karst U (2006) Anal Bioanal Chem 386:1701–1708
Jurva U, Wikstrom HV, Weidolf L, Bruins AP (2003) Rapid Commun Mass Spectrom 17:800–810
Jurva U, Wikstrom HV, Bruins AP (2000) Rapid Commun Mass Spectrom 14:529–533
Fujinari EM, Courthaudon LO (1992) J Chromatogr 592:209–214
Laks S, Pelander A, Vuori E, Ali-Tolppa E, Sippola E, Ojanpera I (2004) Anal Chem 76:7375–7379
Edlund PO, Baranczewski P (2004) J Pharm Biomed Anal 34:1079–1090
Lobinski R, Schaumloffel D, Szpunar J (2006) Mass Spectrom Rev 25:255–289
Jensen BP, Smith CJ, Bailey CJ, Rodgers C, Wilson ID, Nicholson JK (2005) Rapid Commun Mass Spectrom 19:519–524
Solon EG, Balani SK, Lee FW (2002) Current Drug Metabolism 3:451–462
Caprioli RM, Farmer TB, Gile J (1997) Anal Chem 69:4751–4760
Hsieh Y, Chen J, Korfmacher WA (2006) J Pharmacol Toxicol Methods
Stoeckli M, Staab D, Schweitzer A (2007) Int J Mass Spectrom 260:195–202
Signor L, Staack RF, Varesio E, Hopfgartner G, Starke V, Richter (2007) J Mass Spectrom, in press
Marshall P, Heudi O, McKeown S, Amour A, Abou-Shakra F (2002) Rapid Commun Mass Spectrom 16:220–228
Idborg H, Edlund PO, Jacobsson SP (2004) Rapid Commun Mass Spectrom 18:944–954
Varesio E, Staack RF, Hopfgartner G, Maurer HH, Bonner R, Burton LL (2005) Proceedings of the 53rd ASMS Conference on Mass Spectrometry and Allied topics San Antonio, TX, USA
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Staack, R.F., Hopfgartner, G. New analytical strategies in studying drug metabolism. Anal Bioanal Chem 388, 1365–1380 (2007). https://doi.org/10.1007/s00216-007-1367-z
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DOI: https://doi.org/10.1007/s00216-007-1367-z