The present study aims to investigate the preclinical intestinal absorption of bis(7)-tacrine (B7T) using different absorption models. In addition, potential intestinal and liver first-pass metabolism was evaluated by in vitro incubation of B7T with rat intestine and liver microsome. Results showed that the permeability of B7T across artificial membrane was pH dependent with rapid diffusion achieved at both pH 6.8 and 7.4. However, the absorptive permeability of B7T in Caco-2 cell model was substantially lower than that in the artificial membrane accompanied with over 56% of B7T being trapped within Caco-2 cells. In the rat in situ intestinal perfusion model, B7T was subject to an extensive intestinal extraction (>90%) with extremely low concentration of B7T detected in mesenteric blood, which was further found to be associated with the high tissue binding (99.9%) of B7T. In vitro incubation of B7T with rat liver and intestinal microsomes revealed that hydroxylation of B7T might mainly occur in rat liver rather than intestine. In conclusion, B7T is expected to have a low oral bioavailability in vivo, which may be due to its poor intestinal permeability, significant tissue binding and hepatic hydroxylation metabolism. © 2008.