DIFFERENTIAL-EFFECTS OF ACYCLOTHYMIDINE, A POTENT PYRIMIDINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR, ON THE PHARMACOKINETICS OF DOXIFLURIDINE IN RABBITS VIA ORAL-ADMINISTRATION

Acyclothymidine (AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl)uracil), a p otent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), was co-administered with 5'-deoxy-5-fluorouridine (5'-DFUR), a PyNPase act ivating prodrug of 5-fluorouracil (5-FU), to rabbits. The absorption a nd pharmacokinetic parameters of 5'-DFUR and its active metabolite 5-F U, after administration of 5'-DFUR in combination with AcyT, were eval uated in the animals. Animals were given an oral or intravenous admini stration of 5'-DFUR (50 mg/kg) in combination with an equimolar dose o f AcyT (40 mg/kg). The half-lives (t1/2) of 5'-DFUR and 5-FU in plasma were 16.8 and 11.5 min, respectively. AUC (area under the plasma conc entration-time curve) of 5'-DFUR and 5-FU following the oral administr ation of 5'-DFUR (50 mg/kg) was 1710 and 24.3 mug-min/ml, respectively . After the oral co-administration of 5'-DFUR and AcyT (at a molar rat io of 1:1), the AUC values for 5'-DFUR and 5-FU increased to 2680 and to 121.1 mug-min/ml, respectively. However, this combination had littl e effect on the t1/2 of 5'-DFUR.