Received for publication December 18, 2006.
Revised March 12, 2007.
Accepted for publication March 14, 2007.

Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 and its Active N-oxide Metabolite TG100855

Abstract

TG100435 is a novel multi-targeted, orally active protein tyrosine kinase (PTK) 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) in human, dog and rat. TG100855 is 2-9 times more potent than the parent compound. FMOs 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 folds greater than TG100435 in rat and dog after oral dosing of TG100435. Since TG100435 is predominately 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.

Key words: anticancer agents, flavin-containing monooxygenase, inhibition, metabolite identification, oral absorption, pharmacokinetics