Simultaneous Evaluation of Intestinal Absorption and Hepatic Extraction of 5-Fluorouracil Using Portal-Systemic Concentration Difference by Short-Period Double Dosing in a Single Conscious Rat

The intestinal local absorption and the hepatic local disposition of 5-fluorouracil (5-FU) in a single conscious rat was investigated by the simultaneous sampling of portal and systemic bloods (PS method). The portal blood flow rate, measured using a compact electromagnetic flow-meter, was estimated to be 15.3±2.2ml/min per body weight (250g). The portal vein and the femoral artery of the rat were cannulated to simultaneously obtain blood samples from two sites. 5-FU (30mg/kg) was administered first intraarterially, and subsequently orally 90 min after intraarterial administration to a single conscious rat (short-period double dosing; DD). Concentrations of 5-FU in the portal and arterial bloods were determined by HPLC. The local absorption ratio (Fa) and the absolute bioavailability (F) were 71.2±15.4 and 25.1±13.2%, respectively. Consequently, the hepatic extraction ratio (FH=F/Fa) was estimated to be 34.9±14.4%. The mean local absorption time (ta) and the mean absorption time (MAT) were 37.5±15.5 and 31.4±13.7min, respectively and they were statistically the same. In conclusion, a PS method by short-period double dosing (PS-DD method) has been developed to evaluate the first-pass effect, separating the intestinal absorption and hepatic elimination of a drug in a single conscious rat. It was demonstrated by applying PS-DD method that the low bioavailability of 5-FU can be explained by the large hepatic first-pass extraction, and that the large inter-individual variation in bioavailability of 5-FU is caused mainly by a large variation in the hepatic first-pass effect. The large variation in ta (or MAT) was predicted to be due to a variation in the gastric emptying time.