Identification of Drug Metabolites

The metabolite characterization of a new chemical entity (NCE) in various drug discovery stages is crucial in assessment of the safety of a drug for human use [108,120-125]. The identification of metabolites may reveal the metabol-ically labile portions of a molecule in a particular drug series. This information can be used by the synthetic chemists to synthesize compounds that are less susceptible to metabolism and, consequently, have a lower elimination rate and a longer half-life. 

TABLE 7-9. Assignment of the Fragment Ions Observed in the Product Ion Spectrum of Compound A, C24H26N03F3, Using Q-TOF II 

Fragment Ion Observed Formula Theoretical Mass Error 

Source Reprinted from reference 131, with permission of the American Society for Pharmacology and Experimental Therapeutics. 

TABLE 7-10. Most Abundant and Structure Characteristic Fragment Ions Observed in the Product Ion Mass Spectra of Compound A and Its Metabolites B-J 

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The Use of Target-Compound Analysis and LC-MS-MS for the Identification of Drug Metabolites... 

De Maio, W., Hoffmann, M., Carbonara, M., Moore, R., Mutlib, A., and Talaat, R. E. (2008). Identification of drug metabolites by UPLC-MS with isotope pattern directed mass chromatograms and UPLC with radioactivity flow detection. In Proceedings of the 56th ASMS Conference on Mass Spectrometry and Allied Topics. ASMS, Denver, CO. 

Corcoran, O., Nicholson, J. K., Lenz, E. M., Abou-Shakra, F., Castro-Perez, J., Sage, A. B., and Wilson, I. D. (2000). 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. 14 2377-2384. 

Beattie, I. G. Blake, T. X 1989. The structural identification of drug metabolites using thermospray liquid chromatography/mass spectrometry. Biomed. Environ. Mass Spectrom., 18, 872-877. 

Lee, M. S. Yost, R. A. 1988. Rapid identification of drug metabolites with tandem mass spectrometry. Biomed. Env. Mass Spectrom., 15,193-204. 

Lopez, L. L. Yu, X. Cui, D. Davis, M. R. 1998. Identification of drug metabolites in biological matrices by intelligent automated liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom., 12,1756-1760. 

The use of LC-NMR as an analytical tool in combinatorial chemistry remains limited. Its major application within the pharmaceutical industry is in the identification of drug metabolites.38 For this purpose LC-NMR has been further coupled to a mass spectrometer to generate an LC-NMR-MS system.43 The combination of the three techniques provides a powerful tool for structural characterization. 

Other detection principles have been applied to HPLC, e.g. conductivity, radioactivity, infra-red, and photoconductivity detectors. Such detectors are not widely used in drug analysis but can find application in special circumstances (e.g. the identification of drug metabolites arising from a radiolabelled drug by radioactivity detection). 

G.J. Dear, J. Ayrton, R. Plumb, I.J. Fraser, Rapid identification of drug metabolites using capillary LC-ion-trap MS, Rapid Commun. Mass Spectrom., 13 (1999) 456. 

Lee, M.S. Yost, R.A. Rapid Identification of Drug Metabolites with Tandem Mass Spectrometry, . Biomed. Environ. Mass Spectrom. 15, 193-204 (1988). 

Stable isotope labeling in conjunction with MS has been widely used for the identification of drug metabolites since late 1970s. In addition, stable isotope-labeled drugs... 

The advent of all the new ion sources and mass analyzers, along with the recent development in data-acquisition and handling software, have significantly improved quality and detailed information acquired for identification of unknown structures. These methods can be readily used for rapid frontline identification of drug metabolite structures in early drug discovery. 

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