DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on March 22, 2006; DOI: 10.1124/dmd.105.008367

0090-9556/06/3406-901-905$20.00
DMD 34:901-905, 2006

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.008367v1
34/6/901    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, C.
Right arrow Articles by Kumar, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, C.
Right arrow Articles by Kumar, G.
SHORT COMMUNICATION

IDENTIFICATION OF A NOVEL IN VITRO METABONATE FROM LIVER MICROSOMAL INCUBATIONS

Chun Li, Sekhar Surapaneni, QingPing Zeng, Brian Marquez, David Chow, and Gondi Kumar

Department of Pharmacokinetics and Drug Metabolism (C.L., S.S., G.K.) and Department of Chemistry Research and Development (Q.Z., B.M., D.C.), Amgen Inc., Thousand Oaks, California

In vitro drug metabolism studies during the early drug discovery stage are becoming increasingly important. With the increasing demand for high throughput and quick turnaround time for in vitro metabolism studies, however, careful examination of the results and proper design of the experiments are still crucial. In this communication, we report the identification and mechanism of formation of a novel metabonate from incubations of a diamine-containing compound with liver microsomes. The metabonate appeared to be the major product, and its formation was NADPH- and microsomal protein-dependent. Liquid chromatography/mass spectrometry and NMR analysis of the metabonate indicated an extra carbon and unusual formation of an imidazolidine ring. Further studies revealed that this metabonate was not a true biotransformation product from the diamine compound itself in the microsomal incubation, but rather a product resulting from a condensation reaction between the compound and a metabolite of the solvent (alcohol) used in the incubation. When the microsomal incubations contained a small amount of methanol or ethanol as solvent, the alcohols were metabolized to formaldehyde or acetaldehyde, which then condensed with the diamine compound through an imine intermediate to form the metabonate. The compound itself was metabolically stable in vitro when acetonitrile or dimethyl sulfoxide was used as solvent. During the study of in vitro microsomal stability and metabolite identification of amine-containing compounds, the use of alcohol as solvent should be avoided.

Address correspondence to: Chun Li, Mail Stop: 30E-2-C, Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA, 91320-1799. E-mail: chunl{at}amgen.com




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
R. S. Obach
Glycerolysis of Acyl Glucuronides as an Artifact of in Vitro Drug Metabolism Incubations
Drug Metab. Dispos., August 1, 2009; 37(8): 1581 - 1586.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.