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.
OBJECTIVE
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 portal and systemic bloods in conscious rats (PS method).


METHODS
5'-DFUR (100 mg/kg) alone (Group A), or 5'-DFUR + UR (100 mg/kg each) (Group B) was orally administered to conscious rats. The portal and arterial bloods were simultaneously withdrawn from two canulas at appropriate time intervals, and blood concentrations of 5'-DFUR, 5-FU, UR and uracil (U) were assayed by HPLC. The concentration-time profiles of these drugs and its metabolites were analyzed by local moment analysis.


RESULTS
UR coadministration made the local absorption ratio (Fa) of 5'-DFUR decrease significantly from 60.1 +/- 10.5% to 38.0 +/- 18.6% of dose. Though the local absorption ratios (Fm(a)) 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 portal blood, and Fm(a) of U was estimated to be 41.9 +/- 26.8% of UR in Group B.


CONCLUSIONS
It is predicted that a large portion of 5-FU generated from 5'-DFUR is further degraded in the intestine in Group A, and U generated from UR blocks 5-FU degradation in the intestine and the systemic circulation in Group B.
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Y
Y
Sawai
K
K
Yamaoka
T
T
Nakagawa
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics; D001158:Arteries; D004347:Drug Interactions; D005467:Floxuridine / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D011168:Portal System / Q000378:metabolism*; D011169:Portal Vein; D051381:Rats; D017208:Rats, Wistar; D014529:Uridine / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005467:Floxuridine; D005472:Fluorouracil; C025034:doxifluridine; D014529:Uridine