Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (F_a · F_g) and hepatic (F_h) availability after oral administration should be evaluated. Usually, F_a · F_g of drug is calculated from pharmacokinetic parameters after intravenous and oral administration. This approach is influenced markedly by the estimated value of F_h, which varies with the hepatic blood flow used in the calculations. In this study, portal vein-cannulated rats were used to calculate the F_a · F_g of drugs from a single oral dosing experiment without data from intravenous injection. Portal vein-cannulated rats were prepared by a new operative method that enables stable portal vein blood flow. This surgery had no effects on hepatic blood flow and metabolic activity. Our method for calculating F_a · F_g was validated by determining both portal and systemic plasma concentration profiles of various drugs possessing different pharmacokinetic properties after oral administration to the portal vein-cannulated rats. Simulation of portal and systemic plasma concentrations by physiologically based pharmacokinetic modeling indicated that the balance of the absorption rate constant (k_a) and elimination rate constant (k_e) resulted in different patterns in portal and systemic plasma concentration-time profiles. This study is expected to provide a new experimental animal model that enables identification of the factors that limit oral bioavailability and to provide pharmacokinetic information on the oral absorption process of drugs during drug discovery.