Au J L, Wientjes M G, Bramer S L
College of Pharmacy, Ohio State University, Columbus 43210.
Cancer Chemother Pharmacol. 1988;22(1):5-10. doi: 10.1007/BF00254172.
Uridine (UR) inhibits the metabolic activation of 5'-deoxy-5-fluorouridine (dFUR) to 5-fluorouracil (FU) by the intestinal pyrimidine nucleoside phosphorylases and could potentially reduce its intestinal toxicity. This study examined the effect of UR coadministration on the absorption and disposition of an oral dose of dFUR. Rats were given dFUR alone (500 mg kg-1) and dFUR (300 mg kg-1) plus UR (4.5 g kg-1) in a random crossover experiment. Simultaneous injection of a tracer dose of [6-3H]dFUR was used to asses the total body clearance (Cl) of dFUR. The absorption of UR was rapid and variable. The UR dose produced a maximal blood concentration of 80 micrograms/ml for UR and 100 micrograms/ml for its metabolite uracil (U). The absorption of dFUR was slower than UR, as indicated by its later time of maximal concentration. UR did not alter the Cl of dFUR, but reduced the absorption rate of dFUR from the gastrointestinal tract and significantly reduced the absolute oral bioavailability of dFUR from 55.2% to 33.4%. The effects of UR coadministration on the dFUR metabolite FU were opposite to those on dFUR; the FU availability was increased sixfold, and the elimination of FU was reduced. Based on the known competition between pyrimidine bases for their saturable metabolic enzymes, the increase in FU availability by UR coadministration was likely due to a competitive inhibition of FU metabolism by U. This study established the complex pharmacokinetic interactions between dFUR and UR and between their metabolites, which may be important in the modulation of dFUR activity by UR.
尿苷（UR）可抑制肠道嘧啶核苷磷酸化酶将5'-脱氧-5-氟尿苷（dFUR）代谢活化为5-氟尿嘧啶（FU），并有可能降低其肠道毒性。本研究考察了联合给予UR对口服剂量dFUR吸收和处置的影响。在一项随机交叉实验中，给大鼠单独给予dFUR（500 mg·kg-1）以及dFUR（300 mg·kg-1）加UR（4.5 g·kg-1）。同时注射示踪剂量的[6-3H]dFUR用于评估dFUR的全身清除率（Cl）。UR的吸收迅速且存在个体差异。UR剂量产生的UR最大血药浓度为80微克/毫升，其代谢产物尿嘧啶（U）为100微克/毫升。dFUR的吸收比UR慢，这由其达到最大浓度的时间较晚表明。UR未改变dFUR的Cl，但降低了dFUR从胃肠道的吸收速率，并显著降低了dFUR的绝对口服生物利用度，从55.2%降至33.4%。联合给予UR对dFUR代谢产物FU的影响与对dFUR的影响相反；FU的可利用性增加了6倍，且FU的消除减少。基于嘧啶碱基对其饱和代谢酶的已知竞争关系，联合给予UR导致FU可利用性增加可能是由于U对FU代谢的竞争性抑制。本研究确立了dFUR与UR及其代谢产物之间复杂的药代动力学相互作用，这在UR调节dFUR活性方面可能很重要。
