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Comparison of the in vitro metabolism of TG100435 and TG100855 by human liver, intestine and lung microsomes
Author(s) -
Kousba Ahmed A,
Soll Richard,
Hu Steven,
Tabak Arek,
Yee Shiyin
Publication year - 2006
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.20.5.lb108
Subject(s) - microsome , metabolism , in vitro , chemistry , enzyme , biochemistry , small intestine , lung , isozyme , medicine
TG100435, a novel multi‐targeted src+ kinase inhibitor, is an orally active anti‐cancer agent. Our previous studies indicated that TG100435 and TG100855 (N‐oxide of TG100435) are metabolically interconverted by FMO and CYP enzymes, respectively. In the current study, the potential capacity of human liver, intestinal and lung microsomes to metabolize TG100435 and TG100855 were investigated. The studied tissues suggested that TG100435 undergoes metabolic oxidation to TG100855 and TG100855 undergoes metabolic reduction to TG100435. The estimated intrinsic clearance (Vmax/km) values (μl/min/mg protein) are shown in the table below. The FMO related N‐oxidation of TG100435 was mainly contributed by liver and intestine and the reduction of TG100855, although slower, was contributed by all tissues studied.