Abstract
DX-9065a, a newly synthesized anticoagulant that selectively inhibits factor Xa, is a zwitterion and has characteristics of high water solubility and low lipophilicity. We predicted the fraction absorbed (Fa) of DX-9065a to be approximately 15-35% in humans, based on the boundary layer theory using the intestinal perfusion method in rats. However, human oral bioavailability was 2-3% in clinical trials, and the result of actual human bioavailability was lower than that of the predicted Fa. Thus, in this report, the reason for low oral bioavailability of DX-9065a was examined by in vitro and in vivo experiments. The factors affecting oral bioavailability of DX-9065a were not the hepatic first-pass effect, degradation of the drug in intestinal fluid, nor the interaction of the drug with the intestinal mucin. Furthermore, no effect of P-gp efflux was observed. Oral absorption of the drug in rats with bile duct ligation was significantly higher than that in normal rats with bioavailability of 17 and 3%, respectively. It was confirmed that bile acids inhibited DX-9065a absorption because DX-9065a interacted with bile acids to form insoluble complexes. The results suggest that the complex formation of DX-9065a with bile acids in the intestinal tract is an important factor affecting absorption of DX-9065a.
