Influence of the routes of continuous intrahepatic infusion of 5‐fluorouracil on its pharmacokinetics

Continuous infusion chemotherapy via hepatic artery using newly available mechanical devices is frequently used to treat hepatic metastases to achieve a high concentration of 5‐fluorouracil (5‐FUra) in the hepatic circulation while minimizing systemic exposure. We compared four routes of intrahepatic administration to find out the best one in the canine model. To ascertain this data, 5‐FUra (30 mg/kg) was given as a continuous infusion over a 3 hr period into either a systemic vein (femoral), portal vein, hepatic artery, or hepatic artery distal to its ligation after hepatic dearterialization. A total of eight dogs were studied. During 5‐FUra infusion, concomitant blood samples were taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, 60, 120, and 180 min. 5‐FUra levels were determined in plasma by high‐performance liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data described by a multicompartmental model, including the measured flows, had separate hepatic arterial and portal compartments with elimination from each described by linear kinetics. Mean area under the curve values in μ/ml × min and the ratios of the systemic/hepatic vein areas following 5‐FUra infusion via systemic, portal vein, hepatic artery, or hepatic artery after dearterialization routes were: 975/539 (R = 1.80), 939/748 (R = 1.35), 211/454 (R = 0.46), and 562/1,424 (R = 0.39). The results indicated that the administration of 5‐FUra via the hepatic arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest systemic/hepatic vein exposure ratio, followed by intra‐arterial route, while systemic and portal vein routes were not nearly as advantageous as the intra‐arterial routes.