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Review Article

From definition to implementation: a cross-industry perspective of past, current and future MIST strategies

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Pages 605-622 | Received 17 Dec 2010, Accepted 08 Feb 2011, Published online: 29 Mar 2011

References

  • Allan G, Davis J, Dickins M, Gardner I, Jenkins T, Jones H, Webster R, Westgate H. (2008). Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man. Xenobiotica 38:620–640.
  • Anderson S, Luffer-Atlas D, Knadler MP. (2009). Predicting circulating human metabolites: how good are we? Chem Res Toxicol 22:243–256.
  • Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M. (2007). Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25:903–910.
  • Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA. (2002). Drug metabolites in safety testing. Toxicol Appl Pharmacol 182:188–196.
  • Bales JR, Higham DP, Howe I, Nicholson JK, Sadler PJ. (1984b). Use of high-resolution proton nuclear magnetic resonance spectroscopy for rapid multi-component analysis of urine. Clin Chem 30:426–432.
  • Bales JR, Sadler PJ, Nicholson JK, Timbrell JA. (1984a). Urinary excretion of acetaminophen and its metabolites as studied by proton NMR spectroscopy. Clin Chem 30:1631–1636.
  • Boernsen KO, Floeckher JM, Bruin GJ. (2000). Use of a microplate scintillation counter as a radioactivity detector for miniaturized separation techniques in drug metabolism. Anal Chem 72:3956–3959.
  • Brolén G, Sivertsson L, Björquist P, Eriksson G, Ek M, Semb H, Johansson I, Andersson TB, Ingelman-Sundberg M, Heins N. (2010). Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage. J Biotechnol 145:284–294.
  • Buchholz BA, Fultz E, Haack KW, Vogel JS, Gilman SD, Gee SJ, Hammock BD, Hui X, Wester RC, Maibach HI. (1999). HPLC-accelerator MS measurement of atrazine metabolites in human urine after dermal exposure. Anal Chem 71:3519–3525.
  • Caceres-Cortes J, Reily MD. (2010). NMR spectroscopy as a tool to close the gap on metabolite characterization under MIST. Bioanalysis 2:1263–1276.
  • Castro-Perez J, Plumb R, Granger JH, Beattie I, Joncour K, Wright A. (2005). Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. Rapid Commun Mass Spectrom 19:843–848.
  • Covey TR, Crowther JB, Dewey EA, Henion JD. (1985). Thermospray liquid chromatography/mass spectrometry determination of drugs and their metabolites in biological fluids. Anal Chem 57:474–481.
  • Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T, Vianello R. (2005). MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J Med Chem 48:6970–6979.
  • Cuyckens F, Koppen V, Kembuegler R, Leclercq L. (2008). Improved liquid chromatography–online radioactivity detection for metabolite profiling. J Chromatogr A 1209:128–135.
  • Dalvie D, Obach RS, Kang P, Prakash C, Loi CM, Hurst S, Nedderman A, Goulet L, Smith E, Bu HZ, Smith DA. (2009). Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol 22:357–368.
  • Davis-Bruno KL, Atrakchi A. (2006). A regulatory perspective on issues and approaches in characterizing human metabolites. Chem Res Toxicol 19:1561–1563.
  • de Vlieger JS, Kolkman AJ, Ampt KA, Commandeur JN, Vermeulen NP, Kool J, Wijmenga SS, Niessen WM, Irth H, Honing M. (2010). Determination and identification of estrogenic compounds generated with biosynthetic enzymes using hyphenated screening assays, high resolution mass spectrometry and off-line NMR. J Chromatogr B Analyt Technol Biomed Life Sci 878:667–674.
  • Dear GJ, Patel N, Kelly PJ, Webber L, Yung M. (2006). TopCount coupled to ultra-performance liquid chromatography for the profiling of radiolabeled drug metabolites in complex biological samples. J Chromatogr B Analyt Technol Biomed Life Sci 844:96–103.
  • Dear GJ, Patel N, Weightman A, Pirard H, Talvitie M. (2008b). Utilizing a −100 degrees C microplate CCD Imager, yttrium silicate coated 384-microplates and ultra-performance liquid chromatography for improved profiling of radiolabeled drug metabolites in complex biological samples. J Chromatogr B Analyt Technol Biomed Life Sci 868:49–57.
  • Dear GJ, Roberts AD, Beaumont C, North SE. (2008a). Evaluation of preparative high performance liquid chromatography and cryoprobe-nuclear magnetic resonance spectroscopy for the early quantitative estimation of drug metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 876:182–190.
  • Desmoulin F, Gilard V, Malet-Martino M, Martino R. (2002). Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos 30:1221–1229.
  • Driscoll JL, Hayner NT, Williams-Holland R, Spies-Karotkin G, Galletti PM, Jauregui HO. (1982). Phenolsulfonphthalein (phenol red) metabolism in primary monolayer cultures of adult rat hepatocytes. In Vitro 18:835–842.
  • Espina R, Yu L, Wang J, Tong Z, Vashishtha S, Talaat R, Scatina J, Mutlib A. (2009). Nuclear magnetic resonance spectroscopy as a quantitative tool to determine the concentrations of biologically produced metabolites: implications in metabolites in safety testing. Chem Res Toxicol 22:299–310.
  • Falck D, de Vlieger JS, Niessen WM, Kool J, Honing M, Giera M, Irth H. (2010). Development of an online p38a mitogen-activated protein kinase binding assay and integration of LC-HR-MS. Anal Bioanal Chem 398:1771–1780.
  • FDA Guidance for Industry. Safety Testing of Drug Metabolites. (2008). Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf (accessed February 2008).
  • Gao H, Deng S, Obach RS. (2010). A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. Drug Metab Dispos 38:2147–2156.
  • Garner RC, Goris I, Laenen AA, Vanhoutte E, Meuldermans W, Gregory S, Garner JV, Leong D, Whattam M, Calam A, Snel CA. (2002). Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study-experience with 14C-labeled®-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (R115777), a farnesyl transferase inhibitor. Drug Metab Dispos 30:823–830.
  • Guengerich FP. (2002). Update information on human P450s. Drug Metab Rev 34:7–15.
  • Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards D. (2010). Use of the Entero-Test®, a simple approach for the non-invasive capture and qualitative characterisation of biliary metabolites in man. J Clin Pharmacol, in press.
  • Hamilton RA, Garnett WR, Kline BJ. (1981). Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther 29:408–413.
  • Hughes SC, Shardlow PC, Hollis FJ, Scott RJ, Motivaras DS, Allen A, Rousell VM. (2008). Metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid, in humans. Drug Metab Dispos 36:2337–2344.
  • Humphreys WG, Unger SE. (2006). Safety assessment of drug metabolites: characterization of chemically stable metabolites. Chem Res Toxicol 19:1564–1569.
  • ICH Topic M3 (R2). (2009). Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf (accessed June 2009).
  • Ismail IM, Dear GJ, Roberts AD, Plumb RS, Ayrtont J, Sweatman BC, Bowers GD. (2002). N–O Glucuronidation: a major human metabolic pathway in the elimination of two novel anti-convulsant drug candidates. Xenobiotica 32:29–43.
  • Jackson PJ, Brownsill RD, Taylor AR, Walther B. (1995). Use of electrospray ionisation and neutral loss liquid chromatography/tandem mass spectrometry in drug metabolism studies. J Mass Spectrom 20:446–451.
  • Jensen J, Hyllner J, Björquist P. (2009). Human embryonic stem cell technologies and drug discovery. J Cell Physiol 219:513–519.
  • Johnson KA, Plumb R. (2005). Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS. J Pharm Biomed Anal 39:805–810.
  • Kall MA, Gordon B, Laakso S, Freisleben A, Hucker R, Fischmann S, Globig S, Sennbro C-J, Jansat JM, Mulder H, Thomas E, Brundy-Kloeppel M, Luedtke S, Knutsson M, Pusecker K, White SA, Lausecker B, Mokrzycki-Issartel N, Romero F, Anderson MP, Knebel N, de Zwart M, Schmidt D, van Amsterdam P, Abbott R, Boulanger P, Timmerman P. (2010). Best practices in a tiered approach to metabolite quantitation: views and recommendations of the European Bioanalysis Forum. Bioanalysis 2:1185–1194.
  • Kovscsa H, Moskaua D, Spraul M. (2005). Cryogenically cooled probes—a leap in NMR technology. Prog NMR Spectrosc 46:131–155.
  • Lappin G, Garner RC. (2005). The use of accelerator mass spectrometry to obtain early human ADME/PK data. Expert Opin Drug Metab Toxicol 1:23–31.
  • Lappin G, Rowland M, Garner RC. (2006). The use of isotopes in the determination of absolute bioavailability of drugs in humans. Expert Opin Drug Metab Toxicol 2:419–427.
  • Lappin G, Seymour M. (2010). Addressing metabolite safety during first-in-man studies using 14C-labeled drug and accelerator mass spectrometry. Bioanalysis 2:1315–1324.
  • Lappin G, Stevens L. (2008). Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Expert Opin Drug Metab Toxicol 4:1021–1033.
  • Lee MS, Kerns EH. (1999). LC/MS applications in drug development. Mass Spectrom Rev 18:187–279.
  • Lenz EM, Wilson ID, Wright B, Partridge EA, Rodgers CT, Haycock PR, Lindon JC, Nicholson JK. (2002). 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 28:31–43.
  • Liberman RG, Skipper PL, Prakash C, Shaffer CL, Flarakos J, Tannenbaum SR. (2007). BEAMS Lab: novel approaches to finding a balance between throughput and sensitivity. Nucl Instr Meth Phys Res B 259:773–778.
  • Liberman RG, Tannenbaum SR, Hughey BJ, Shefer RE, Klinkowstein RE, Prakash C, Harriman SP, Skipper PL. (2004). An interface for direct analysis of (14)C in nonvolatile samples by accelerator mass spectrometry. Anal Chem 76:328–334.
  • Lin C, Li Y, McGlotten J, Morton JB, Symchowicz S. (1977). Isolation and identification of the major metabolite of albuterol in human urine. Drug Metab Dispos 5:234–238.
  • Lindon JC, Nicholson JK, Wilson ID. (1996). Direct coupling of chromatographic separations to NMR spectroscopy. J Prog Nuclear Magn Spectros 29:1–49.
  • Ma S, Li Z, Lee KJ, Chowdhury SK. (2010). Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds. Chem Res Toxicol 23:1871–1873.
  • Malet-Martino M, Gilard V, Desmoulin F, Martino R. (2006). Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs. Clin Chim Acta 366:61–73.
  • Malz F, Jancke H. (2005). Validation of quantitative NMR. J Pharm Biomed Anal 38:813–823.
  • McDowall RD. (1989). Sample preparation for biomedical analysis. J Chromatogr 492:3–58.
  • McIlhenny HM. (1971). Metabolism of [14C]verapamil. J Med Chem 14:1178–1184.
  • Mortishire-Smith RJ, O’Connor D, Castro-Perez JM, Kirby J. (2005). Accelerated throughput metabolic route screening in early drug discovery using high-resolution liquid chromatography/quadrupole time-of-flight mass spectrometry and automated data analysis. Rapid Commun Mass Spectrom 19:2659–2670.
  • Mutlib A, Espina R, Vishwanathan K, Babalola K, Chen Z, Dehnhardt C, Venkatesan A, Mansour T, Chaudhary I, Talaat R, Scatina J. (2011). Application of quantitative NMR in pharmacological evaluation of biologically generated metabolites: implications in drug discovery. Drug Metab Dispos 39:106–116.
  • Nassar AE, Bjorge SM, Lee DY. (2003). On-line liquid chromatography–accurate radioisotope counting coupled with a radioactivity detector and mass spectrometer for metabolite identification in drug discovery and development. Anal Chem 75:785–790.
  • Nassar AE, Lee DY. (2007). Novel approach to performing metabolite identification in drug metabolism. J Chromatogr Sci 45:113–119.
  • Nedderman AN, Savage ME, White KL, Walker DK. (2004). The use of 96-well Scintiplates to facilitate definitive metabolism studies for drug candidates. J Pharm Biomed Anal 34:607–617.
  • Nicholls AW, Farrant RD, Shockcor JP, Unger SE, Wilson ID, Lindon JC, Nicholson JK. (1997). NMR and HPLC-NMR spectroscopic studies of futile deacetylation in paracetamol metabolites in rat and man. J Pharm Biomed Anal 15:901–910.
  • Plumb RS, Ayrton J, Dear GJ, Sweatman BC, Ismail IM. (1999). 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 13:845–854.
  • Powley MW, Frederick CB, Sistare FD, DeGeorge JJ. (2009). Safety assessment of drug metabolites: implications of regulatory guidance and potential application of genetically engineered mouse models that express human P450s. Chem Res Toxicol 22:257–262.
  • Prakash C, Soliman V. (1997). Metabolism and excretion of a novel antianxiety drug candidate, CP-93,393, in Long Evans rats. Differentiation of regioisomeric glucuronides by LC/MS/MS. Drug Metab Dispos 25:1288–1297.
  • Ramanathan R, Josephs JL, Jemal M, Arnold M, Humphreys WG. (2010). Novel MS solutions inspired by MIST. Bioanalysis 2:1291–1313.
  • Robison TW, Jacobs A. (2009). Metabolites in safety testing. Bioanalysis 1:1193–1200.
  • Roffey SJ, Obach RS, Gedge JI, Smith DA. (2007). What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 39:17–43.
  • Smith DA, Obach RS. (2006). Metabolites and safety: what are the concerns, and how should we address them? Chem Res Toxicol 19:1570–1579.
  • Smith DA, Obach RS. (2009). Metabolites in safety testing (MIST): considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chem Res Toxicol 22:267–279.
  • Smith DA, Obach RS. (2005). Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab Dispos 33:1409–1417.
  • Spraul M, Hofmann M, Dvortsak P, Nicholson JK, Wilson ID. (1993). High-performance liquid chromatography coupled to high-field proton nuclear magnetic resonance spectroscopy: application to the urinary metabolites of ibuprofen. Anal Chem 65:327–330.
  • Srivastava A, Lian LY, Maggs JL, Chaponda M, Pirmohamed M, Williams DP, Park BK. (2010). Quantifying the metabolic activation of nevirapine in patients by integrated applications of NMR and mass spectrometries. Drug Metab Dispos 38:122–132.
  • Testa B, Balmat AL, Long A, Judson P. (2005). Predicting drug metabolism—an evaluation of the expert system METEOR. Chem Biodivers 2:872–885.
  • Vishwanathan K, Babalola K, Wang J, Espina R, Yu L, Adedoyin A, Talaat R, Mutlib A, Scatina J. (2009). Obtaining exposures of metabolites in preclinical species through plasma pooling and quantitative NMR: addressing metabolites in safety testing (MIST) guidance without using radiolabeled compounds and chemically synthesized metabolite standards. Chem Res Toxicol 22:311–322.
  • Walker D, Brady J, Dalvie D, Davis J, Dowty M, Duncan JN, Nedderman A, Obach RS, Wright P. (2009). A holistic strategy for characterizing the safety of metabolites through drug discovery and development. Chem Res Toxicol 22:1653–1662.
  • Walker GS, O’Connell TN. (2008). Comparison of LC-NMR and conventional NMR for structure elucidation in drug metabolism studies. Expert Opin Drug Metab Toxicol 4:1295–1305.
  • Walker GS, Ryder TF, Sharma R, Smith EB, Freund A. (2010). Validation of isolated metabolites from drug metabolism studies as analytical standards by quantitative NMR. Drug Metab Dispos, Published online before print 22 November 2010.
  • Wang WW, Khetani SR, Krzyzewski S, Duignan DB, Obach RS. (2010). Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites. Drug Metab Dispos 38:1900–1905.
  • Weidolf LO, Lee ED, Henion JD. (1988). Determination of boldenone sulfoconjugate and related steroid sulfates in equine urine by high-performance liquid chromatography/tandem mass spectrometry. Biomed Environ Mass Spectrom 15:283–289.
  • Wilson ID, Nicholson JK, Hofmann M, Spraul M, Lindon JC. (1993). Investigation of the human metabolism of antipyrine using coupled liquid chromatography and nuclear magnetic resonance spectroscopy of urine. J Chromatogr 617:324–328.
  • Wright P, Miao Z, Shilliday B. (2009). Metabolite quantitation: detector technology and MIST implications. Bioanalysis 1:831–845.
  • Xu L, Adams B, Jeliazkova-Mecheva VV, Trimble L, Kwei G, Harsch A. (2008). Identification of novel metabolites of colchicine in rat bile facilitated by enhanced online radiometric detection. Drug Metab Dispos 36:731–739.
  • Yi P, Luffer-Atlas D. (2010). A radiocalibration method with pseudo internal standard to estimate circulating metabolite concentrations. Bioanalysis 2:1195–1210.
  • Yoshizato K, Tateno C. (2009). In vivo modeling of human liver for pharmacological study using humanized mouse. Expert Opin Drug Metab Toxicol 5:1435–1446.
  • Young GC, Corless S, Felgate CC, Colthup PV. (2008). Comparison of a 250 kV single-stage accelerator mass spectrometer with a 5 MV tandem accelerator mass spectrometer–fitness for purpose in bioanalysis. Rapid Commun Mass Spectrom 22:4035–4042.
  • Young GC, Ellis WJ. (2007). AMS in drug development at GSK. Nuc Inst Methods Phys Res B 259:752–757.
  • Yu AM, Idle JR, Gonzalez FJ. (2004). Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates. Drug Metab Rev 36:243–277.
  • Yu C, Chen CL, Gorycki FL, Neiss TG. (2007). A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of liquid chromatography/mass spectrometry and radiometric detection. Rapid Commun Mass Spectrom 21:497–502.
  • Yu H, Bischoff D, Tweedie D. (2010). Challenges and solutions to metabolites in safety testing: impact of the international conference on harmonization M3(R2) guidance. Expert Opin Drug Metab Toxicol 6:1539–1549.
  • Zhang H, Zhang D, Ray K. (2003). A software filter to remove interference ions from drug metabolites in accurate mass liquid chromatography/mass spectrometric analyses. J Mass Spectrom 38:1110–1112.
  • Zhang D, Raghavan N, Chando T, Gambardella J, Fu Y, Zhang D, Unger SE, Humphreys WG. (2007). LC-MS/MS-based approach for obtaining exposure estimates of metabolites in early clinical trials using radioactive metabolites as reference standards. Drug Metab Lett 1:293–298.
  • Zhang N, Fountain ST, Bi H, Rossi DT. (2000). Quantification and rapid metabolite identification in drug discovery using API time-of-flight LC/MS. Anal Chem 72:800–806.
  • Zhu M, Zhang D, Skiles GL. (2005). Quantification and structural elucidation of low quantities of radiolabeled metabolites using microplate scintillation counting techniques in conjunction with LC-MS. In: Chowdhury SK, ed. Identification and Quantification of Drugs, Metabolites and Metabolising Enzymes by LC-MS. Amsterdam: Elsevier, pp. 195–223.
  • Zhu M, Zhang D, Zhang H, Shyu WC. (2009c). Integrated strategies for assessment of metabolite exposure in humans during drug development: analytical challenges and clinical development considerations. Biopharm Drug Dispos 30:163–184.
  • Zhu P, Ding W, Tong W, Ghosal A, Alton K, Chowdhury S. (2009b). A retention-time-shift-tolerant background subtraction and noise reduction algorithm (BgS-NoRA) for extraction of drug metabolites in liquid chromatography/mass spectrometry data from biological matrices. Rapid Commun Mass Spectrom 23:1563–1572.
  • Zhu P, Tong W, Alton K, Chowdhury S. (2009a). An accurate-mass-based spectral-averaging isotope-pattern-filtering algorithm for extraction of drug metabolites possessing a distinct isotope pattern from LC-MS data. Anal Chem 81:5910–5917.
  • Ziarelli F, Viel S, Caldarelli S, Sobieski DN, Augustine MP. (2008). General implementation of the ERETIC method for pulsed field gradient probe heads. J Magn Reson 194:307–312.

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