Smith D E, Brenner D E, Knutsen C A, Deremer S J, Terrio P A, Johnson N J, Stetson P L, Ensminger W D
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Drug Metab Dispos. 1993 Mar-Apr;21(2):277-83.
The pharmacokinetics of 5-fluorouracil (FUra) were studied alone and in the presence of either bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) in five mixed breed hounds. FUra was administered intravenously over 1 min as a 5 mg/kg dose in all three treatments. BrdUrd or IdUrd was infused intravenously at 2.5 mg/hr.kg x 6 hr and FUra was given 3 hr into the 6-hr infusion of thymidine analog. Serial blood samples were obtained for 3 hr prior to and after FUra dosing. Plasma concentrations of FUra, BrdUrd and bromouracil (BrUra), and IdUrd and iodouracil (IUra) were measured by reversed-phase HPLC. Concomitant administration of BrdUrd or IdUrd resulted in substantial changes in the kinetics of FUra. In particular, the total plasma clearance of FUra was decreased and area under the plasma concentration-time curve was increased. There were also significant changes in the volume of distribution steady-state, and in the mean residence time and half-life of FUra. The data show that FUra had little or no effect on the disposition of BrdUrd or IdUrd. In contrast, FUra had a significant effect on the disposition of BrUra and IUra going to form catabolic products. The observed pharmacokinetic interaction in dogs is probably due to a competition between BrUra (or IUra) and FUra for the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase. This kinetic interaction was mutual and of a smaller magnitude for FUra + BrdUrd than for FUra + IdUrd.
在五只杂种猎犬中，单独研究了5-氟尿嘧啶（FUra）的药代动力学，以及在存在溴脱氧尿苷（BrdUrd）或碘脱氧尿苷（IdUrd）的情况下的药代动力学。在所有三种处理中，FUra均以5mg/kg的剂量在1分钟内静脉给药。BrdUrd或IdUrd以2.5mg/hr.kg×6小时的速率静脉输注，并且在胸苷类似物的6小时输注过程中3小时给予FUra。在FUra给药前后3小时采集系列血样。通过反相高效液相色谱法测量血浆中FUra、BrdUrd和溴尿嘧啶（BrUra），以及IdUrd和碘尿嘧啶（IUra）的浓度。BrdUrd或IdUrd的联合给药导致FUra的动力学发生显著变化。特别是，FUra的总血浆清除率降低，血浆浓度-时间曲线下面积增加。FUra的分布稳态容积、平均驻留时间和半衰期也有显著变化。数据表明，FUra对BrdUrd或IdUrd的处置几乎没有影响。相反，FUra对形成分解代谢产物的BrUra和IUra的处置有显著影响。在犬中观察到的药代动力学相互作用可能是由于BrUra（或IUra）与FUra竞争限速分解代谢酶二氢嘧啶脱氢酶所致。这种动力学相互作用是相互的，并且对于FUra + BrdUrd比对于FUra + IdUrd的幅度更小。
