Hepatobiliary toxicity of 5-fluoro-2'-deoxyuridine. Intra-arterial versus portal venous routes of infusion.

Biliary sclerosis remains the dose-limiting toxicity in a subset of patients receiving hepatic arterial (HA) floxuridine (FUDR) for the treatment of hepatic malignancy. To investigate the etiology of FUDR-associated sclerosing cholangitis, portal vein catheters were placed in mixed-breed hounds (N = 4) and connected to an implanted infusion pump system. Floxuridine 0.3 mg/kg/day was infused for 49 to 77 days each, as a continuous infusion. Cholangiograms were performed before and after infusion, and weekly liver function tests were obtained. The results were compared to dogs (N = 6) that received HA FUDR 0.3 mg/kg/d x 30 days, and dogs (N = 5) that received HA saline for 100 days. Elevation in the serum glutamic pyruvic transaminase and alkaline phosphatase, indistinguishable from the HA group, was seen in all four dogs with portal vein infusion. Maximum bilirubin levels ranged from 0.6 to 3.0 (mean 1.7), compared to a range of 6.4 to 28 (mean 13.4) for the HA dogs. Cholangiograms demonstrated hepatic volume loss consistent with hepatocellular injury, but no biliary sclerosis. These data suggest that sclerosing cholangitis resulting from intra-arterial infusion of FUDR is unlikely to be due to metabolites of the drug excreted in the bile, but due to direct toxicity to the biliary tree.