Effect of Acute Hepatic Failure on Epirubicin Pharmacokinetics after Intrahepatic Arterial Injection in Rats

Abstract

In the case of cancer chemotherapy for hepatocellular carcinoma, anthracycline anticancer agents such as epirubicin are widely used, and have typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. The anthracyclines are eliminated primarily by the liver, and the use of these drugs in patients with hepatic failure can be difficult. In this study, we investigated the effect of acute hepatic failure on the pharmacokinetics of epirubicin after i.a. injection in rats. Experimental acute hepatic failure was induced by carbon tetrachloride-treatment. Epirubicin was injected into the hepatic artery or the saphenous vein of the rats at a dose of 2 mg/kg. After both intravenous (i.v.) and i.a. injection, the serum concentration and the AUC_0—24 of epirubicin in hepatic failure rats were significantly higher than the values in control rats. The AUC_0—24 ratio of hepatic failure (i.a.) to control (i.a.) was higher than the ratio of hepatic failure (i.v.) to control (i.v.). These results suggest that the influence of hepatic failure on serum epirubicin concentration is larger with the i.a. route than with the i.v. route. The liver concentration of epirubicin after i.a. administration in hepatic failure rats was significantly lower than that in control rats. This result suggests that the effect of the liver-selective drug targeting after i.a. injection in hepatic failure rats is lower than in normal rats. Therefore, we should be careful when administering epirubicin by the i.a. route in patients with acute hepatic failure.