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 +/- 2.2 ml/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 (30 mg/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 (F[H] = F/Fa) was estimated to be 34.9 +/- 14.4%. The mean local absorption time (t[a]) and the mean absorption time (MAT) were 37.5 +/- 15.5 and 31.4 +/- 13.7 min, 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 t(a) (or MAT) was predicted to be due to a variation in the gastric emptying time.