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 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 (t1/2) 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 micrograms.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 micrograms.min/ml, respectively. However, this combination had little effect on the t1/2 of 5'-DFUR.
Hamada
A
A
Department of Pharmacy, Kumamoto University Hospital, Japan.
Fukushima
S
S
Morinaga
A
A
Saneyoshi
M
M
Kawaguchi
T
T
Nakano
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005467:Floxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000493:pharmacokinetics; D008297:Male; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors*; D057845:Pyrimidine Phosphorylases; D011817:Rabbits; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005467:Floxuridine; D014498:Uracil; C046151:N-(2-(hydroxyethoxy)methyl)-5-methyluracil; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D005472:Fluorouracil; C025034:doxifluridine