SIMULTANEOUS EVALUATION OF INTESTINAL-ABSORPTION AND HEPATIC EXTRACTION OF 5-FLUOROURACIL USING PORTAL-SYSTEMIC CONCENTRATION DIFFERENCE BYSHORT-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 ,compact electromagnetic flow-meter, was estimated to be 15.3 +/- 2.2 ml/min per body weight (250 g). The portal vein and the f emoral artery of the rat were cannulated to simultaneously obtain bloo d samples from two sites, 5-FU (30 mg/kg) was administered first intra arterially, and subsequently orally 90 min after intraarterial adminis tration to a single conscious rat (short-period double dosing; DD). Co ncentrations of 5-FU in the portal and arterial bloods were determined by HPLC. The local absorption ratio (F-a) and the absolute bioavailab ility (F) were 71.2 +/- 15.4 and 25.1 +/- 13.2% respectively. Conseque ntly, the hepatic extraction ratio (F-H=F/F-a) was estimated to be 34. 9 +/- 14.4%. The mean local absorption time ((t) over bar(a)) and the mean absorption time (MAT) were 37.5 +/- 15.5 and 31.4 +/- 13.7 min, r espectively 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 absorpti on and hepatic elimination of a drug in a single conscious rat. It was demonstrated by applying PS-DD method that the love. bioavailability of 5-FU can be explained by the large hepatic first-pass extraction, a nd that the large inter-individual variation in bioavailability of 5-F U is caused mainly by a large variation in the hepatic first-pass effe ct. The large variation in (t) over bar(a) (or MAT) was predicted to b e due to a variation in the gastric emptying time.