EFFECT OF COADMINISTERED URIDINE ON INTESTINAL FIRST-PASS METABOLISM OF 5'-DEOXY-5-FLUOROURIDINE IN CONSCIOUS RATS - AN EVALUATION BY METHOD OF PORTAL-SYSTEMIC CONCENTRATION DIFFERENCE

Purpose. The effect of uridine (UR) coadministration on the intestinal metabolism from 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU) was evaluated by a method of concentration difference between p ortal and systemic bloods in conscious rats (PS method). Methods. 5'-D FUR (100 mg/kg) alone (Group A), or 5'-DFUR + UR (100 mg/kg each) (Gro up B) was orally administered to conscious rats. The portal and arteri al bloods were simultaneously withdrawn from two canulas at appropriat e time intervals, and blood concentrations of 5'-DFUR, 5-FU, UR and ur acil (U) were assayed by HPLC. The concentration-time profiles of thes e drugs and its metabolites were analyzed by local moment analysis. Re sults. UR coadministration made the local absorption ratio (F-a) of 5' -DFUR decrease significantly from 60.1 +/- 10.5% to 38.0 +/- 18.6% of dose. Though the local absorption ratios (F-a(m)) of the metabolite (5 -FU) were the same between Group A and Group B (8.3 +/- 1.9 and 8.7 +/ - 4.0% of 5'-DFUR, respectively), AUC of arterial 5-FU in Group B was 5 times greater than that in Group A. UR was not detected in the porta l blood, and F-a(m) of U was estimated to be 41.9 +/- 26.8% of UR in G roup B. Conclusions, It is predicted that a large portion of 5-FU gene rated from 5'-DFUR is further degraded in the intestine in Group A, an d U generated from UR blocks 5-FU degradation in the intestine and the systemic circulation in Group B.