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

Abstract

ABSTRACT:To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (F a ⅐ F g ) and hepatic (F h ) availability after oral administration should be evaluated. Usually, F a ⅐ 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 ⅐ 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 ⅐ 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.

In Vivo Assessment of the Impact of Efflux Transporter on Oral Drug Absorption Using Portal Vein–Cannulated Rats

“…The oral and intravenous administration studies were conducted on the 9th day after the surgery. On the 9th day, no significant differences were observed in the physiologic condition of cannulated and untreated rats (Matsuda et al, 2012).…”

“…The surgical procedure for catheter insertion was reported previously (Matsuda et al, 2012). Animals were implanted with catheters in the portal vein as follows.…”

“…As Q por, the value of 32.9 ml/min/kg was used, as calculated in our previous report by assuming that Fa·Fg of antipyrine was 1 (Matsuda et al, 2012).…”

“…The use of portal vein-cannulated rats, and monitoring both portal and systemic blood concentrations of the drug, enables calculation of Fa·Fg from a single oral dosing study without the need for intravenous injection (Matsuda et al, 2012). Calculation of Fa·Fg using portal vein-cannulated rats shows less variability than conducting typical kinetic analyses, because our calculation method is less sensitive to interindividual fluctuation in portal blood flow.…”

Novel, Selective, and Developable Dopamine D3 Antagonists with a Modified “Amino” Region

“…The F ub in blood was 22 %, and the corresponding value in brain was 42 %. Finally, when the compound was tested in a portal‐vein‐cannulated rat model, it demonstrated a moderate fraction absorbed ( F a ) at 54 %, low steady‐state volume of distribution ( V ss =2.6 L kg −1 ), and high clearance in blood, as expected from the in vitro parameters ( Cl b =73 mL min −1 kg −1 ), leading to a half‐life ( t 1/2 ) of 0.6 h. Given moderate hepatic extraction ( E h ) at 0.6, the total bioavailability ( F ) of the compound was equal to 29 %. In general, all the compounds tested showed relatively good levels of F a and low V ss values, suggesting the suitability of this class for further studies.…”