Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclopyrimidinenucleosides in intestinal tissue homogenates.
This study examined the inhibitory effect of acyclopyrimidinenucleosides on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in intestinal tissue derived from rabbit, rat, mouse, and human. 5-Bromoacyclouridine, 5-fluoroacyclouridine, acyclouridine, and 5-nitroacyclouridine showed little or only moderate effect, but acyclothymidine [5-methyl-1-(2'-hydroxyethoxymethyl)uracil] showed strong inhibitory effect on 5'-DFUR phosphorolysis in intestinal tissue homogenates derived from human. In the absence of inhibitor (acyclothymidine), the Vmax of 5'-DFUR phosphorolysis was 2.66 mumol/min and the Km was 0.57 mM in human intestinal homogenates. The Vmax was unaltered by increased inhibitor concentration. The maximal inhibitory effect of acyclothymidine on 5'-DFUR phosphorolysis in rat homogenates was over 90%. The Ki/Km was 0.63 in human, 2.14 in rabbit, 1.09 x 10(-2) in rat, and 1.71 x 10(-2) in mouse. These data show that acyclothymidine is a competitive inhibitor of 5'-DFUR phosphorolysis, and that it can inhibit not only uridine phosphorylase but also thymidine phosphorylase.
Hamada
A
A
Department of Pharmacy, Kumamoto University Hospital, Japan.
Fukushima
S
S
Saneyoshi
M
M
Kawaguchi
T
T
Nakano
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D005467:Floxuridine / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010758:Phosphorus / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014543:Uridine Phosphorylase / Q000378:metabolism
D000970:Antineoplastic Agents; D011744:Pyrimidinones; D005467:Floxuridine; D010758:Phosphorus; D014543:Uridine Phosphorylase; C025034:doxifluridine