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 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 (ta) 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 ta, 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 approximately 7% of 5'-DFUR arrived as 5-FU at the portal system. The mean local absorption time (tam) 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.
Sawai
Y
Y
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Yamaoka
K
K
Takemura
A
A
Nakagawa
T
T
D000818:Animals; D001682:Biological Availability; D005467:Floxuridine / Q000378:metabolism*; D005472:Fluorouracil / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D005467:Floxuridine; D005472:Fluorouracil