Differential Effects of Acyclothymidine, a Potent Pyrimidine Nucleoside Phosphorylase Inhibitor, on the Pharmacokinetics of Doxifluridine in Rabbits via Oral Administration

抄録

Acyclothymidine (AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl)uracil), a potent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), was co-administered with 5'-deoxy-5-fluorouridine (5'-DFUR), a PyNPase activating prodrug of 5-fluorouracil (5-FU), to rabbits. The absorption and pharmacokinetic parameters of 5'-DFUR and its active metabolite 5-FU, after administration of 5'-DFUR in combination with AcyT, were evaluated in the animals. Animals were given an oral or intravenous administration of 5'-DFUR (50 mg/kg) in combination with an equimolar dose of AcyT (40 mg/kg). The half-lives (t_1/2) of 5'-DFUR and 5-FU in plasma were 16.8 and 11.5 min, respectively. AUC (area under the plasma concentration-time curve) of 5'-DFUR and 5-FU following the oral administration of 5'-DFUR (50 mg/kg) was 1710 and 24.3 μg·min/ml, respectively. After the oral co-administration of 5'-DFUR and AcyT (at a molar ratio of 1 : 1), the AUC values for 5'-DFUR and 5-FU increased to 2680 and to 121.1 μg·min/ml, respectively. However, this combination had little effect on the t_1/2 of 5'-DFUR.