Modulation of the pharmacokinetics of 5'-deoxy-5-fluorouridine and 5-fluorouracil in rats by oral co-administration of acyclothymidine.
The effect of an inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), acyclothymidine (AcyT), on the pharmacokinetics of 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU) was investigated in an oral co-administration of 5'-DFUR and AcyT in rats. AcyT increased the maximal plasma concentration (Cmax) and apparent absorption rate constant (ka) of 5'-DFUR, as expected, but the increase in AUC (area under the curve) was not significant. It was expected that AcyT would only inhibit the phosphorolytic degradation of 5'-DFUR to 5-FU, but the effect was more evident on the pharmacokinetic parameters of 5-FU than on those of 5'-DFUR. AcyT also increased AUC and Cmax of 5-FU when orally co-administered with 5-FU. An inhibitory effect of AcyT on the enzymatic degradation of 5-FU in rat liver and intestinal extract was investigated. AcyT inhibited the degradation in intestinal extract but not in the liver. The result suggests that orally administered AcyT affects the pharmacokinetics of 5-FU partly by inhibiting 5-FU degradation in the process of intestinal absorption as well as by acting as an inhibitor of PyNPase.
Hamada
A
A
Department of Pharmacy, Kumamoto University Hospital, Japan.
Fukushima
S
S
Saneyoshi
M
M
Shimizu
S
S
Kawaguchi
T
T
Nakano
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005467:Floxuridine / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000378:metabolism / Q000493:pharmacokinetics*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors; D057845:Pyrimidine Phosphorylases; D051381:Rats; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005467:Floxuridine; D014498:Uracil; C046151:N-(2-(hydroxyethoxy)methyl)-5-methyluracil; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D005472:Fluorouracil; C025034:doxifluridine