Effect of acute hepatic failure on the hepatic first‐pass effect of 5‐fluorouracil in rats

Objectives In cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil is widely used and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver and so the hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil may be lower in patients with hepatic failure, and systemic toxicity may not be reduced. In this study, we have investigated the effect of acute hepatic failure on the first‐pass effect of 5‐fluorouracil in rats. Methods Experimental acute hepatic failure was induced by treatment with carbon tetrachloride (CCl₄). 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of rats at a dose of 1.25 mg/kg. Key findings Hepatic availability in 50% CCl₄‐treated (severe hepatic failure) rats was higher than in controls. Conclusions The hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil was lower in severe hepatic failure. Therefore, the reducing effect of the systemic toxicity after intrahepatic arterial administration may be lower in severe hepatic failure.