RT Journal Article
SR Electronic
T1 Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2231
OP 2238
DO 10.1124/dmd.112.048223
VO 40
IS 12
A1 Yoshiki Matsuda
A1 Yoshihiro Konno
A1 Masahiro Satsukawa
A1 Taro Kobayashi
A1 Yu Takimoto
A1 Kunihiko Morisaki
A1 Shinji Yamashita
YR 2012
UL http://dmd.aspetjournals.org/content/40/12/2231.abstract
AB To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (Fa · Fg) and hepatic (Fh) availability after oral administration should be evaluated. Usually, Fa · Fg of drug is calculated from pharmacokinetic parameters after intravenous and oral administration. This approach is influenced markedly by the estimated value of Fh, which varies with the hepatic blood flow used in the calculations. In this study, portal vein-cannulated rats were used to calculate the Fa · Fg 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 Fa · Fg 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 (ka) and elimination rate constant (ke) 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.