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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

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Abstract

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 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 The portal and arterial bloods were simultaneously withdrawn from two canulas at appropriate time intervals, and blood concentrations of 5′-DFUR, 5-FU, UR and uracil (U) were assayed by HPLC.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 (Fa 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 portal blood, and Fa m 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.

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  1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606, Japan

    Yoneichi Sawai, Kiyoshi Yamaoka & Terumichi Nakagawa

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  1. Yoneichi Sawai
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  2. Kiyoshi Yamaoka
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Sawai, Y., Yamaoka, K. & Nakagawa, T. 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. Pharm Res 15, 1007–1011 (1998). https://doi.org/10.1023/A:1011917824836

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