MOMENT ANALYSIS OF INTESTINAL FIRST-PASS METABOLISM BY PORTAL-SYSTEMIC CONCENTRATION DIFFERENCE IN SINGLE CONSCIOUS RAT USING 5'-DEOXY-5-FLUOROURIDINE AND 5-FLUOROURACIL AS MODEL-DRUG SYSTEM

Intestinal first-pass metabolism was evaluated in a single conscious r at based on a difference in concentrations of parent drug and its meta bolite between the portal and systemic bloods (P-S difference method). 5'-Deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU) were sel ected as model drug (prodrug of 5-FU) and metabolite pair. The portal vein and the femoral artery of the rat were cannulated so blood sample s could be obtained simultaneously from the two sites. 5'-DFUR (100 mg /kg) was administered intraarterially or orally. Concentrations of 5'- DFUR and 5-FU in the portal and arterial samples were assayed by HPLC. The concentration-time profiles of 5'-DFUR and 5-FU were analyzed by local moment analysis. The extent of systemic bioavailability (F) of 5 '-DFUR was estimated to be 75.8%. After oral administration, the local absorption ratio (F-a) and the mean local absorption time ((t) over b ar(a)) of 5'-DFUR were estimated to be 65.8 +/- 7.3% of dose and 74.0 +/- 21.7 min, respectively. The F-a value was close to F-a which sugge sts that the metabolic conversion from 5'-DFUR to 5-FU is not extensiv e in the liver. The mean absorption time (MAT), calculated to be 76.3 min, almost coincided with (t) over bar(a), which suggests that the me an hepatic transit time is negligible in this experimental scale. The local absorption ratio of metabolite (F-a(m))was 6.8 +/- 1.7% of orall y administered 5'-DFUR, which means that similar to 7% of 5'-DFUR arri ved as 5-FU at the portal system. The mean local absorption time ((t) over bar(a)(m)) of 5-FU was estimated to be 75.5 min, which is close t o that (74.0 min) of 5'-DFUR. Local moment analysis based on P-S diffe rence enabled simultaneous estimation of the local absorption kinetics of a parent compound and the intestinal generation of metabolites by separating the intestinal first-pass metabolism of a drug from the sub sequent disposition through the liver and in the systemic circulation.