Kinetic impact of presystemic intestinal metabolism on drug absorption: experiment and data analysis for the prediction of in vivo absorption from in vitro data

Drug Metab Pharmacokinet. 2002;17(6):496-506. doi: 10.2133/dmpk.17.496.


Orally administered drugs suffer from attack by metabolic enzymes not only in the liver, but also in the gastrointestine during the absorption process across the intestinal tissue. Although kinetic study on hepatic metabolism has been done well, the intestinal metabolism has not been well focused on compared with hepatic metabolism. In order to emphasize the role of intestinal metabolism in drug absorption and bioavailability, I have reviewed the experimental methods for intestinal absorption and metabolism, and the data analysis. Since Klippert et al. reported the prediction of intestinal first-pass effect of phenacetin in the rat from enzyme kinetic data in 1982, several reports have showed a good prediction, but others have not. Although intestinal absorption is an integrated process of transport (transporters) and metabolism (metabolic enzymes), most of the researchers missed the pathway of intestinal drug absorption and applied the kinetic model effective on only systemic metabolism to presystemic intestinal metabolism for their analysis of intestinal metabolism of orally administered drugs. A kinetic model, which incorporated factors of membrane transport, metabolic activity and protein binding, was structured to compare the equations in the reported models. In conclusion, we need more studies including kinetic modeling and experiments to understand the impact of intestinal metabolism on drug absorption. That knowledge must lead to the construction of ADME in silico (e-ADME).