Metabolite identification in drug discovery

Current Opinion in Drug Discovery and Development

Volumn 6, Issue 1, 2003, Pages 57-65

  Watt, Alan P ^a   Mortishire Smith, Russell J ^a   Gerhard, Ute ^a   Thomas, Steven R ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

Drug metabolism; Mass spectrometry; Metabolite identification; Metabolite refinement; Nuclear magnetic resonance; Structural elucidation

Indexed keywords

10 HYDROXYCAMPTOTHECIN; CYTOCHROME P450; DRUG METABOLITE; ETODOLAC; S 19812; TACRINE; UNCLASSIFIED DRUG;

DRUG IDENTIFICATION; DRUG ISOLATION; DRUG METABOLISM; DRUG STRUCTURE; ENZYME METABOLISM; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL; MASS SPECTROMETRY; MICROSOME; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTON NUCLEAR MAGNETIC RESONANCE; REVIEW; SOLID PHASE EXTRACTION; STRUCTURE ANALYSIS; TECHNIQUE;

ANIMALS; BIOTRANSFORMATION; ELECTROPHORESIS, CAPILLARY; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; PHARMACOLOGY;

EID: 0037277751     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (57)

1. Park BK, Naisbitt DJ, Gordon SF, Kitteringham NR, Pirmohamed M: Metabolic activation in drug allergies. Toxicology (2001) 158:11-23. This article reviews the link between hypersensitivity and metabolic bioactivation in compounds, and metabolic pathways implicated in idiosyncratic toxicity.
2. Clarke SE, Jeffrey P: Utility of metabolic stability screening: Comparison of in vitro and in vivo clearance. Xenobiotica (2001) 31:591-598.
3. Masimirembwa CM, Thompson R, Andersson TB: In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery. Comb Chem High Throughput Screen (2001) 4:245-263.
4. 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.
5. Imamura Y, Wu X, Noda A, Noda H: Side-chain metabolism of propranolol: Involvement of monoamine oxidase and mitochondrial aldehyde dehydrogenase in the metabolism of N-desisopropylpropranolol to naphthoxylactic acid in rat liver. Life Sci (2002) 70:2687-2697.
6. Hoekstra R, Chamuleau RA: Recent developments on human cell lines for the bioartificial liver. Int J Artif Organs (2002) 25:182-191.
7. Nyberg SL, Hay EJ, Ramin KD, Rosen CB: Successful pregnancy after porcine bioartificial liver treatment and liver transplantation for fulminant hepatic failure. Liver Transplant (2002) 8:169-170.
8. Pilard S, Caradec F, Jackson P, Luijten W: Identification of an N-(hydroxysulfonyl)oxy metabolite using in vitro microorganism screening, high-resolution and tandem electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom (2000) 14:2362-2366.
9. 19F NMR spectroscopy for rapid screening of cell cultures for models of mammalian drug metabolism. Analyst (2001) 126:2103-2106.
10. Mayhew MP, Reipa V, Holden MJ, Vilker VL: Improving the cytochrome P450 enzyme system for electrode-driven biocatalysis of styrene epoxidation. Biotech Prog (2000) 16:610-616.
11. Shin YG, Bolton JL, van Breemen RB: Screening drugs for metabolic stability using pulsed ultrafiltration mass spectrometry. Comb Chem High Throughput Screen (2002) 5:59-64. Liver microsomes trapped in a chamber with an ultrafiltration membrane are flow-injected with drug and NADPH cofactor. This provides convenient access to metabolic stability, via LC-MS/MS analysis of the ultrafiltrate.
12. Platzer P, Thalhammer T, Reznicek G, Hamilton G, Zhang R, Jager W: Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver. Int J Oncol (2001) 19:1287-1293.
13. Bolden RD, Hoke SH II, Eichhold TH, McCauley-Myers DL, Wehmeyer KR: Semi-automated liquid-liquid back-extraction in a 96-well format to decrease sample preparation time for the determination of dextromethorphan and dextrorphan in human plasma. J Chromatogr B (2002) 772:1-10.
14. Plumb RS, Ayrton J, Dear GJ, Sweatman BC, Ismail IM: The use of preparative high performance liquid chromatography with tandem mass spectrometric directed fraction collection for the isolation and characterisation of drug metabolites in urine by nuclear magnetic resonance spectroscopy and liquid chromatography/sequential mass spectrometry. Rapid Commun Mass Spectrom (1999) 13:845-854. Important new technology using mass-directed fractionation to isolate metabolites from complex biomatrices.
15. Ulrich S: Solid-phase microextraction in biomedical analysis. J Chromatogr A (2000) 902:167-194. Comprehensive review of the theory and application of SPME in a bioanalytical arena.
16. Walles M, Mullett WM, Levsen K, Borlak J, Wunsch G, Pawliszyn J: Verapamil drug metabolism studies by automated in-tube solid phase microextraction. J Pharm Biomed Anal (2002) 30:307-319.
17. Diaz A, Ventura F, Galceran MT: Simultaneous determination of estrogenic short ethoxy chain nonylphenols and their acidic metabolites in water by an in-sample derivatization/solid-phase microextraction method. Anal Chem (2002) 74:3869-3876.
18. Gunaratna C, Kissinger PT: Application of microdialysis to study the in vitro metabolism of drugs in liver microsomes. J Pharm Biomed Anal (1997)16:239-248.
19. Liu DQ, Hop CE, Beconi MG, Mao A, Chiu SH: Use of on-line hydrogen/deuterium exchange to facilitate metabolite identification. Rapid Commun Mass Spectrom (2001) 15:1832-1839.
20. Luu NC, Iyer RA, Anders MW, Ridge DP: Fourier-transform ion cyclotron resonance mass spectrometric studies of elimination reactions of anionic bases with metabolites of a fluorinated anesthetic agent: Towards modeling bioactivation in the gas phase. Int J Mass Spectrom (2000) 195/196:203-213.
21. Liu DQ, Xia YQ, Bakhtiar R: Use of a liquid chromatography/ion trap mass spectrometry/triple quadrupole mass spectrometry system for metabolite identification. Rapid Commun Mass Spectrom (2002) 16:1330-1336.
22. Pinkston JD, Delaney TE, Morand KL, Cooks RG: Supercritical fluid chromatography/mass spectrometry using a quadrupole mass filter/quadrupole ion trap hybrid mass spectrometer with external ion source. Anal Chem (1992) 64:1571-1577.
23. Hager JW: A new linear ion trap mass spectrometer. Rapid Commun Mass Spectrom (2002) 16:512-526. Quadrupole-trap instrument using a standard tandem-MS design, but employing mass-selective axial ion ejection from the final quadrupole. This technique gives high sensitivity product ion scanning.
24. 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.
25. Nicholson JK, Lindon JC, Scarfe GB, Wilson ID, Abou-Shakra F, Sage AB, Castro-Perez J: High-performance liquid chromatography linked to inductively coupled plasma mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry for the simultaneous detection and identification of metabolites of 2-bromo-4-trifluoromethyl. Anal Chem (2001) 73:1491-1494.
26. Corcoran O, Nicholson JK, Lenz EM, Abou-Shakra F, Castro-Perez J, Sage AB, Wilson ID: Directly coupled liquid chromatography with inductively coupled plasma mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry for the identification of drug metabolites in urine: Application to diclofenac using chlorine and sulfur detection. Rapid Commun Mass Spectrom (2000) 14:2377-2384.
27. Sundstrom I, Hedeland M, Bondesson U, Andren PE: 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. Accurate mass (±2.1 ppm) data used in conjunction with collisionally induced dissociation product ion spectra to identify glucuronide conjugates.
28. Poon GK, Chen Q, Teffera Y, Ngui JS, Griffin PR, Braun MP, Doss GA, Freeden C, Steams RA, Evans DC, Baillie TA et al. Bioactivation of diclofenac via benzoquinone imine intermediates - Identification of urinary mercapturic acid derivatives in rats and humans. Drug Metab Dispos (2001) 29:1608-1613. Demonstration of the importance of identification of metabolites formed by glutathione conjugation, leading to delineation of reactive electrophilic intermediates.
29. Ramanathan R, McKenzie DL, 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.
30. Castro-Perez J, Kirby J, Preece S: High-sensitivity LC-MS-MS for the automated identification of drug metabolites. Am Biotechnol Lab (2000) 18:38-44. A first approach to automated analysis, using accurate mass measurement and a comparison of control and metabolized samples to highlight peaks of interest.
31. Strickmann DB, Blaschke G: Capillary electrochromatography-electrospray ionization mass spectrometry for the qualitative investigation of the drug etodolac and its metabolites in biological samples. J Chromatogr B Biomed Appl (2000) 748:213-219.
32. Embrechts J, Lemiere F, van Dongen W, Esmans EL: Equilenin-2′-deoxynucleoside adducts: Analysis with nano-liquid chromatography coupled to nano-electrospray tandem mass spectrometry. J Mass Spectrom (2001) 36:317-328.
33. Keski-Hynnila 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. Application of APPI MS to biological samples.
34. Cappiello A, Famiglini G, Mangani F, Palma P: New trends in the application of electron ionization to liquid chromatography-mass spectrometry interfacing. Mass Spectrom Rev (2001) 20:88-104.
35. Dear G, Plumb R, Mallett D: Use of monolithic silica columns to increase analytical throughput for metabolite identification by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom (2001) 15:152-158. This technology combines a high-resolution separation with high-throughput LC-MS for qualitative analysis.
36. Martino R, Malet-Martino M, Gilard V: Fluorine nuclear magnetic resonance, a privileged tool for metabolic studies of fluoropyrimidine drugs. Curr Drug Metab (2000) 1:271-303.
37. Lenz EM, Wilson ID, Wright B, Partridge EA, Rodgers CT, Haycock PR, Lindon JC, Nicholson JK: A comparison of quantitative NMR and radiolabelling studies of the metabolism and excretion of Statil (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) in the rat. J Pharm Biomed Anal (2002) 28:31-43.
38. 19F-NMR spectroscopy in the investigation of the urinary and biliary excretion of 3,5-, 2,4-ditrifluoromethylbenzoic and pentafluorobenzoic acids in rat. Xenobiotica (2002) 32:605-613.
39. 13C]-4-trifluoromethoxyacetanilide in the rat: Detection and identification of metabolites excreted in the urine by NMR and HPLC-NMR. J Pharm Biomed Anal (2002) 28:875-885.
40. 1H NMR spectroscopic studies of the reactive α-1-O-acyl isomer formed during acyl migration of S-naproxen β-1,-O-acyl glucuronide. Chem Res Toxicol (2001) 14:1363-1370.
41. Ruhl R, Thiel R, Lacker TS, Strohschein S, Albert K, Nau H: Synthesis, high-performance liquid chromatography-nuclear magnetic resonance characterization and pharmacokinetics in mice of CD271 glucuronide. J Chromatogr B Biomed Appl (2001) 757:101-109.
42. Silva Elipe MV, Huskey S-EW, Zhu B: Application of LC-NMR for the study of the volatile metabolite of MK-0869, a substance P receptor antagonist. J Pharm Biomed Anal (2003) 30:1431-1440.
43. Dear GJ, Mallett DN, Higton DM, Roberts AD, Bird SA, Young H, Plumb RS, Ismail IM: The potential of serially coupled alkyl-bonded silica monolithic columns for high resolution separations of pharmaceutical compounds in biological fluids. Chromatographia (2002) 55:177-184.
44. Griffiths L, Horton R: Optimization of LC-NMR. III. Increased signal-to-noise ratio through column trapping. Magnetic Resonance Chem (1998) 36:104-109.
45. Yokoyama Y, Kishi N, Tanaka M, Asakawa N: On-line sample preparation system using column-switching HPLC for the structure elucidation of compounds in mixtures by NMR. Anal Sci (2000) 16:1183-1188. A strategy, commercialized by Bruker, which is likely to be future method of choice for LC-NMR-MS.
46. Bao D, Thanabal V, Pool WF: Determination of tacrine metabolites in microsomal incubate by high performance liquid chromatography-nuclear magnetic resonance/mass spectrometry with a column trapping system. J Pharm Biomed Anal (2002) 28:23-30.
47. Nyberg NT, Baumann H, Kenne L: Application of solid-phase extraction coupled to an NMR flow-probe in the analysis of HPLC fractions. Magnetic Resonance Chem (2001) 39:236-240.
48. Buker Biospin GmbH: Bruker BioSpin announces novel capillary LC-NMR system. Press Release (March 2002), http://www.brukerbiospin. com/nmr/news/pdf_files/caplc-nmr.pdf
49. Schlotterbeck G, Ross A, Hochstrasser R, Senn H, Kuhn T, Marek D, Schett O: High-resolution capillary tube NMR. A miniaturized 5ml high-sensitivity TXI probe for mass-limited samples, off-line LC NMR, and HT NMR. Anal Chem (2002) 74:4464-4471.
50. 1H NMR spectroscopy using a 1 mm microlitre probe. Analyst (2002) 127:582-584.
51. Peck TL, Sweedler JV: The miniaturization of NMR probes hyphenated to capillary scale separations. In: Micro Total Analysis Systems 2001. Ramsey JM, van den Berg A (Eds), Kluwer Academic Publishers, Dordrecht, the Netherlands (2001):417-419.
52. Kautz RA, Lacey ME, Wolters AM, Foret F, Webb AG, Karger BL, Sweedler JV: Sample concentration and separation for nanoliter-volume NMR spectroscopy using capillary isotachophoresis. J Am Chem Soc (2001) 123:3159-3160.
53. Wolters AM, Jayawickrama DA, Larive CK, Sweedler JV: Capillary isotachophoresis/NMR: Extension to trace impurity analysis and improved instrumental coupling. Anal Chem (2002) 74:2306-2313.
54. 13C NMR spectroscopy of urine for metabonomic studies. Anal Chem (2002) 74:4588-4593. While this paper does not specifically address a drug metabolism issue, cryoprobe technology has dramatically improved NMR sensitivity, and will undoubtedly be applied to metabolite identification.
55. Buker Biospin GmbH: Bruker BioSpin introduces the CryoFlowProbe, the world's first cryogenic flow-injection NMR probe. Press Release (March 2002), http.//www.bruker-biospin.com/ nmr/news/pdf_files/cryoflowprb.pdf
56. NMR probes. Varian Inc, Palo Alto, CA, USA. http://www.varianinc.com/cgi.bin/nav?varinc/docs/nmr/products/probes/
57. Bruker Biospin GmbH: SPE boosts LC-NMR performance. Press Release (March 2001), http://www.bruker-biospin.com/nmr/news/ pdf_files/lcnmrms_spe.pdf