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 N-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).

摘要: 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 ( K i ) of against Src, Lyn, Abl, Yes, Lck, and EphB4 range from 13 to 64 nM. has systemic clearance values 20.1, 12.7, 14.5 ml/min/kg oral bioavailability 74%, 23%, 11% in mouse, rat, dog, respectively. Four oxidation metabolites have been found human, rat vitro vivo. ethylpyrrolidine N -oxide 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) rat. TG100855 2 9 times more potent than parent compound. Flavin-containing monooxygenases are primary enzymes mediating biotransformation. Significant conversion observed dog after administration. Systemic exposure 1.1- 2.1-fold greater that dosing TG100435. Since predominantly converted across species vivo vitro, overall animal models may be substantially increased administration