Absorption of CH330331, A Novel 4-Anilinoquinazoline Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase: Comparative Studies using In Vitro, In Situ and In Vivo Models

CH330331 is a prototype of a new class of synthetic small molecule tyrosine kinase inhibitors (TKIs). In vitro Caco-2 cell monolayers, the in situ single-pass rat intestinal perfusion (SPIP) technique with mesenteric vein cannulated and an in vivo animal model were employed to investigate its permeability and transepithelial transport mechanisms. The Caco-2 model showed that the transport of CH330331 across the monolayers from the apical (AP) to basolateral (BL) side was 6- to 10-fold higher than that from the BL to AP side. The apparent permeability coefficient (P-app) values of CH330331 at 5-20 mu g/ml from the AP to BL and from BL to AP side were 5.30-2.21 x 10(-6) cm/s, with a decrease in Papp values from the AP to BL side at increased CH330331 concentrations. In the perfused rat intestinal model, a concentration dependent change in permeability was detected where P-blood at 5 mu g/ml (1.66 +/- 0.69 x 10(-6) cm/s) and 10 mu g/ml (1.80 +/- 0.45 x 10(-6) cm/s) was significantly different from P-blood at 20 mu g/ml (0.98 +/- 0.31 x 10(-6) cm/s, p<0.05). Some inhibitors could also change the transepithelial transport of CH330331. Moreover, the in vivo study showed that the oral bioavailability of CH330331 was 82.7% in the rat. All the results confirmed that the transepithelial transport of CH330331 was rapid and saturable, which might involve an active mechanism. The oral bioavailability of CH330331 was relatively high in vivo. Copyright (C) 2010 John Wiley & Sons, Ltd.