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

Department of Pharmacology and Toxicology [F. P. L., B. S. W., W. M. W.], and Department of Medicine [W. M. W.], University of Louisville, Louisville, Kentucky 40292

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 disappearance of each fluoropyrimidine followed Michaelis-Menten kinetics, as shown previously. 6-Benzyl-2-thiouracil, a thymidine phosphorylase-selective inhibitor, and 1-(2'-deoxy-ß-D-glucopyranosyl)thymine, a uridine phosphorylase-selective inhibitor, each decreased the rate of FdUrd disappearance (apparent K_i, 1.4–1.6 and 3.8 mM, 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 t of disappearance of derived FUra due to its delayed formation. 2,6-Dihydroxypyridine, a uridine phosphorylase-selective inhibitor, decreased the rate of FdUrd disappearance (apparent K_i, 12.4–16.2 µM) and directly inhibited FUra elimination (apparent K_i, 4.3–5.3 µM). 2,4-Dihydroxypyridine, which does not inhibit pyrimidine nucleoside phosphorylases, directly inhibited FUra elimination (apparent K_i, 77 µM) 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.

¹ Present address: Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111.

² Recipient of an Amoco Foundation Graduate Student Fellowship. Present address: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, MD 20892.

³ To whom requests for reprints should be addressed, at the Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292.

Received 10/12/88. Revised 2/15/89. Accepted 2/21/89.