RT Journal Article SR Electronic T1 APPLICATION OF BIOCATALYSIS TO DRUG METABOLISM: PREPARATION OF MAMMALIAN METABOLITES OF A BIARYL-BIS-SULFONAMIDE AMPA (α-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID) RECEPTOR POTENTIATOR USING Actinoplanes missouriensis JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 925 OP 931 DO 10.1124/dmd.106.009522 VO 34 IS 6 A1 Milton Zmijewski A1 Todd A. Gillespie A1 David A. Jackson A1 Douglas F. Schmidt A1 Ping Yi A1 Palaniappan Kulanthaivel YR 2006 UL http://dmd.aspetjournals.org/content/34/6/925.abstract AB LY451395 (2-propanesulfonamide, N-[(2R)-2-[4′-[2-[methylsulfonyl)amino]ethyl][1,1′-biphenyl]-4-yl]propyl]-) is a potent and highly selective potentiator of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. It is a biaryl-bis-sulfonamide and is known to be highly metabolized in preclinical species. In those metabolism studies, the metabolite structures were proposed exclusively by the analysis of mass spectrometric data. Although mass spectrometry is clearly a technique of choice for rapid identification of drug metabolites, occasionally, nuclear magnetic resonance spectroscopy is required to unambiguously assign and characterize, particularly, the regio- and stereochemistry of metabolic changes. Nuclear magnetic resonance spectroscopy, in general, is less sensitive than other detection methods and demands several micrograms of material for the analysis. To support full structure characterization of metabolites by NMR, in this study we demonstrated the application of a microbial-based surrogate biocatalytic system to produce sufficient amounts of the mammalian metabolites of LY451395. The results revealed that incubation of LY451395 with Actinoplanes missouriensis NRRL B3342 generated several metabolites that were previously detected in the in vivo metabolism studies of the preclinical species. Subsequent large-scale bioconversion resulted in the isolation of seven mammalian metabolites in milligram quantities for structural characterization by nuclear magnetic resonance spectroscopy. Furthermore, a selected group of metabolites generated from the microbial conversion served as analytical standards to monitor and quantify drug metabolites during clinical investigations. The American Society for Pharmacology and Experimental Therapeutics