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

Abstract

Intestinal first-pass metabolism was evaluated in a single conscious rat based on a difference in concentrations of parent drug and its metabolite between the portal and systemic bloods (P–S difference method). 5′-Deoxy-5-fluorouridine (5′-DFUR) and 5-fluorouracil (5-FU) were selected as model drug (prodrug of 5-Fu) and metabolite pair. The portal vein and the femoral artery of the rat were cannulated so blood samples 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 (Fa) and the mean local absorption time t¯a of 5′-DFUR were estimated to be 65.8±7.3% of dose and 74.0±21.7 min, respectively. The Fa value was close to F, which suggests that the metabolic conversion from 5′-DFUR to 5-FU is not extensive in the liver. The mean absorption time (MAT), calculated to be 76.3 min, almost coincided with t¯a, which suggests that the mean hepatic transit time is negligible in this experimental scale. The local absorption ratio of metabolite (Fam) was 6.8±1.7% of orally administered 5′-DFUR, which means that ~7% of 5′-DFUR arrived as 5-FU at the portal system. The mean local absorption time t¯am of 5-FU was estimated to be 75.5 min, which is close to that (74.0 min) of 5′-DFUR. Local moment analysis based on P–S difference 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 subsequent disposition through the liver and in the systemic circulation.