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Metabolism of substituted vs. unsubstituted pyridine analogs of NNRTIs
Author(s) -
Wang Jianhong,
Eisenberg Eugene,
Wieman Lani,
Miles Jaclyn,
Zhang Jingyu,
Rhodes Gerry
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb78-c
Subject(s) - pyridine , hydroxylation , chemistry , microsome , in vivo , in vitro , pyridine n oxide , stereochemistry , enzyme , metabolic stability , metabolic pathway , pharmacokinetics , metabolism , medicinal chemistry , biochemistry , pharmacology , biology , microbiology and biotechnology
A new series of NNRTIs with substituted or unsubstituted pyridine has been developed, and members of this series have demonstrated potent activity against NNRTI‐resistant virus. In this study, both in vitro microsomal stability assay and in vivo animal pharmacokinetics study were conducted for selected NNRTIs in order to establish the in vitro‐in vivo correlations. There was a good correlation for the substituted pyridine analogs, but for the unsubstituted pyridine analogs, the in vivo clearance was under‐predicted in vitro . We investigated the metabolic pathways of several substituted pyridine analogs and one unsubstituted pyridine analog. The hydroxylation on the ring and N‐hydroxylation of the amino group were found to be the major metabolic pathways for the substituted pyridine analogs. However, for the unsubstituted pyridine analog, N‐oxide formation was the single most important metabolic pathway. This pathway was under‐represented in the liver microsomes, which indicates that the N‐oxide formation was likely catalyzed by non‐P450 enzyme systems. Further investigations are underway to identify the enzyme system that is responsible for the N‐oxide formation on the unsubstituted pyridines. This research is supported by Gilead Sciences, Inc.