PT  - JOURNAL ARTICLE
AU  - Steven X. Hu
AU  - Richard Soll
AU  - Shiyin Yee
AU  - Daniel L. Lohse
AU  - Ahmed Kousba
AU  - Binqi Zeng
AU  - Xiyun Yu
AU  - Andrew McPherson
AU  - Joel Renick
AU  - Jianguo Cao
AU  - Arek Tabak
AU  - John Hood
AU  - John Doukas
AU  - Glenn Noronha
AU  - Michael Martin
TI  - Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 ([7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active <em>N</em>-Oxide Metabolite TG100855 ([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine)
AID  - 10.1124/dmd.106.014290
DP  - 2007 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 929--936
VI  - 35
IP  - 6
4099  - http://dmd.aspetjournals.org/content/35/6/929.short
4100  - http://dmd.aspetjournals.org/content/35/6/929.full
SO  - Drug Metab Dispos2007 Jun 01; 35
AB  - TG100435 ([7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) is a novel multitargeted, orally active protein tyrosine kinase inhibitor. The inhibition constants (Ki) of TG100435 against Src, Lyn, Abl, Yes, Lck, and EphB4 range from 13 to 64 nM. TG100435 has systemic clearance values of 20.1, 12.7, and 14.5 ml/min/kg and oral bioavailability of 74%, 23%, and 11% in mouse, rat, and dog, respectively. Four oxidation metabolites of TG100435 have been found in human, dog, and rat in vitro and in vivo. The ethylpyrrolidine N-oxide of TG100435 is the predominant metabolite (TG100855; [7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine) in human, dog, and rat. TG100855 is 2 to 9 times more potent than the parent compound. Flavin-containing monooxygenases are the primary enzymes mediating the biotransformation. Significant conversion of TG100435 to TG100855 has been observed in rat and dog after oral administration. Systemic exposure of TG100855 is 1.1- and 2.1-fold greater than that of TG100435 in rat and dog after oral dosing of TG100435. Since TG100435 is predominantly converted to the more potent N-oxide metabolite across species in vivo and in vitro, the overall tyrosine kinase inhibition in animal models may be substantially increased after oral administration of TG100435. The American Society for Pharmacology and Experimental Therapeutics