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

摘要: The breakdown of 5-fluoro-2'-deoxyuridine (FdUrd) to 5-fluorouracil (FUra) is catalyzed by the pyrimidine nucleoside phosphorylases, uridine phosphorylase and thymidine phosphorylase. effects inhibitors on FdUrd FUra elimination isolated perfused rat liver were investigated. inhibitor was injected into perfusion reservoir 5 min before or FUra, serial fluid samples collected for fluoropyrimidine analysis. disappearance each followed Michaelis-Menten kinetics, as shown previously. 6-Benzyl-2-thiouracil, a phosphorylase-selective inhibitor, 1-(2'-deoxy-beta-D-glucopyranosyl)thymine, decreased rate (apparent Ki, 1.4-1.6 3.8 mM, respectively) but had no direct effect disappearance. However, 6-benzyl-2-thiouracil peak concentration derived from administered increased t 1/2 due its delayed formation. 2,6-Dihydroxypyridine, 12.4-16.2 microM) directly inhibited 4.3-5.3 microM). 2,4-Dihydroxypyridine, which does not inhibit 77 also disappearance, possibly product inhibition. It concluded that hepatic slowed some these drugs block well FdUrd, elimination.