Hepatic Fluoropyrimidine Elimination in the Rat Effects of Pyrimidine Nucleoside Phosphorylase Inhibitors on

The breakdown of 5-fluoro-2'-deoxyuridine (FdUrd) to 5-fluorouracil (FUra) is catalyzed by the pyrimidine nucleoside phosphorylases, uridine phosphorylase and thymidine phosphorylase. The effects of nucleoside phosphorylase inhibitors on FdUrd and FUra elimination by the isolated perfused rat liver were investigated. The inhibitor was injected into the perfusion reservoir 5 min before FdUrd or FUra, and serial perfusion fluid samples were collected for fluoropyrimidine analysis. The disap pearance of each fluoropyrimidine followed Michaelis-Menten kinetics, as shown previously. 6-Benzyl-2-thiouracil, a thymidine phosphorylaseselective inhibitor, and l-(2'-deoxy-/3-D-glucopyranosyl)thymine, a uri dine phosphorylase-selective inhibitor, each decreased the rate of FdUrd disappearance (apparent A',-,1.4-1.6 and 3.8 HIM, respectively) but had no direct effect on FUra disappearance. However, 6-benzyl-2-thiouracil decreased the peak concentration of FUra derived from administered FdUrd and increased the /., of disappearance of derived FUra due to its delayed formation. 2,6-Dihydroxypyridine, a uridine phosphorylase-se lective inhibitor, decreased the rate of FdUrd disappearance (apparent A',-,12.4-16.2 MM)and directly inhibited FUra elimination (apparent A,. 4.3-5.3 JÕM). 2,4-Dihydroxypyridine, which does not inhibit pyrimidine nucleoside phosphorylases, directly inhibited FUra elimination (apparent KI, 77 n\i) and also decreased the rate of FdUrd disappearance, possibly due to product (FUra) inhibition. It was concluded that the hepatic elimination of FdUrd is slowed by pyrimidine nucleoside phosphorylase inhibitors and that some of these drugs block FUra, as well as FdUrd, elimination.