Evaluation of relative LC/MS response of metabolites to parent drug in LC/nanospray ionization mass spectrometry: Potential implications in MIST assessment

Journal of Mass Spectrometry

Volumn 46, Issue 12, 2011, Pages 1282-1287

  Schadt, Simone ^a,c   Chen, Lin Zhi ^b   Bischoff, Daniel ^a  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

^c F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

drug development; drug metabolites; MIST; pharmaceutical industry; semi quantitation

Indexed keywords

BIOMOLECULES; DRUG PRODUCTS; FOG; IONIZATION POTENTIAL; MASS SPECTROMETRY; MATRIX ALGEBRA;

BIOLOGICAL MATRIXES; DRUG DEVELOPMENT; DRUG METABOLITES; IONIZATION MASS SPECTROMETRY; NANOELECTROSPRAY IONIZATION MASS SPECTROMETRY; PHARMACEUTICAL COMPOUNDS; PHARMACEUTICAL INDUSTRY; SEMI QUANTITATIONS;

METABOLITES;

DRUG METABOLITE;

ANIMAL EXPERIMENT; ARTICLE; BILE; CHEMICAL STRUCTURE; DOG; DRUG DESIGN; DRUG SAFETY; EVALUATION; FECES; HOMOGENATE; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MINIPIG; MOUSE; NANOSPRAY IONIZATION MASS SPECTROMETRY; NONHUMAN; PLASMA; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; RADIOACTIVITY; RADIOCHROMATOGRAPHY; RAT; SAMPLING; STANDARD; URINE;

EID: 84855272978     PISSN: 10765174     EISSN: 10969888     Source Type: Journal    
DOI: 10.1002/jms.2018     Document Type: Article

References (15)

1. C. E. C. A. Hop, Y. Chen, L. J. Yu,. Uniformity of ionization response of structurally diverse analytes using a chip-based nanoelectrospray ionization source. Rapid Commun. Mass Spectrom. 2005, 19, 3139.
2. FDA US. Guidance for industry: Safety testing of drug metabolites. 2008, available from
3. ICH. Guidance on M3(R2) non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2009, available from:.
4. M. Zhu, D. Zhang, H. Zhang, W. C. Shyu,. Integrated strategies for assessment of metabolite exposure in humans during drug development: Analytical challenges and clinical development considerations. Biopharm. Drug Dispos. 2009, 30, 163.
5. C. P. Yu, C. L. Chen, F. L. Gorycki, T. G. Neiss,. 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. 2007, 21, 497.
6. H. Gao, S. Deng, S. R. Obach,. 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. 2010, 38, 2147.
7. C. E. C. A. Hop,. Use of nano-electrospray for metabolite identification and quantitative absorption, distribution, metabolism and excretion studies. Curr. Drug Metab. 2006, 7, 557.
8. E. R. Wickremsinhe, G. Singh, B. L. Ackermann, T. A. Gillespie, A. K. Chaudhary,. A review of nanoelectrospray ionization applications for drug metabolism and pharmacokinetics. Curr. Drug Metab. 2006, 7, 913.
9. G. A. Valaskovic, L. Utley, M. S. Lee, J. T. Wu,. Ultra-low flow nanospray for the normalization of conventional liquid chromatography/mass spectrometry through equimolar response: Standard-free quantitative estimation of metabolite levels in drug discovery. Rapid Commun. Mass Spectrom. 2006, 20, 1087.
10. R. Ramanathan, R. Zhong, N. Blumenkrantz, S. K. Chowdhury, K. B. Alton,. Response normalized liquid chromatography nanospray ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 2007, 18, 1891.
11. Q. Hu, R. J. Noll, H. Li, A. Makarov,., M. Hardman, R. G. Cooks,. The Orbitrap: A new mass spectrometer. J. Mass Spectrom. 2005, 40, 430.
12. G. A. Schultz, T. N. Corso, S. J. Prosser, S. Zhang,. A fully integrated monolithic microchip electrospray device for mass spectrometry. Anal. Chem. 2000, 72, 4058.
13. S. Ma, Z. Li, K. J. Lee, S. K. Chowdhury,. Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds. Chem. Res. Toxicol. 2010, 23, 1871.
14. S. Ma, S. K. Chowdhury,. Analytical strategies for assessment of human metabolites in preclinical safety testing. Anal. Chem. 2011, 83, 5028.
15. D. Zhang, N. Raghavan, T. Chando, J. Gambardella, Y. Fu, D. Zhang, S. E. Unger, W.G. Humphreys,. LC-MS/MS-based approach for obtaining exposure estimates of metabolites in early clinical trials using radioactive metabolites as reference standards. Drug. Metab. Lett. 2007, 4, 293.