Hepatic Artery Infusion of Doxorubicin with Hepatic Venous Drug Extraction

Abstract

Hepatic artery infusion (HAI) has been used to take advantage of the steep dose-response relationship characteristic of chemotherapeutic agents. Systemic toxicity, however, remains the dose limiting factor for HAI of low hepatic extraction drugs. This investigation compared the pharmacokinetics of doxorubicin administered using a system that combines HAI and hepatic venous drug extraction (HVDE) versus systemic administration without HVDE. HAI was accomplished by transfemoral cannulation of the hepatic artery. HVDE was aided by use of a double-balloon catheter inserted fluoroscopically via femoral vein cutdown into the inferior vena cava. Inflation of the balloons above and below the hepatic veins allowed collection of hepatic venous effluent. Hepatic venous blood was pumped through the double-balloon catheter into an extracorporeal circuit with activated carbon filters to extract drug prior to return to the systemic circulation. Domestic female swine (25-35 kg) received 3 mg/kg doxorubicin over 90 min via HAI. HVDE was performed for 240 min following initiation of HAI (Time 0-240 min). Control swine underwent hepatic venous isolation using the double-balloon catheter without drug filtration and received 3 mg/kg doxorubicin over 90 min via systemic vein (SYSI). Serum and myocardial doxorubicin and doxorubicinol levels were assayed using HPLC. Blood was serially sampled from hepatic vein blood, from the extracorporeal circuit after filtration, and from a systemic artery. Area under the curve (AUC) was integrated from time-concentration plots over Time 0-180 min. During HAI, AUCs (nmole · min) in the hepatic venous effluent, in the extracorporeal circuit after filtration, and in systemic blood were 113 ± 32.0, 12.6 ± 4.82, and 16.9 ± 8.43, respectively. During SYSI, hepatic vein and systemic AUCs were 83.6 ± 22.1 and 270 ± 112, respectively, the later significantly greater (P = 0.017) than that during HAI. After hepatic arterial infusion, cardiac tissue concentrations of doxorubicin and doxorubicinol were 16.8-fold less and >4.0-fold less, respectively, than those after systemic infusion. These data show that HAI with HVDE increases hepatic delivery of doxorubicin with reduced systemic and cardiac drug exposure. This method may be applicable to other drugs poorly extracted by the liver and to clinical situations in which enhanced regional drug delivery is desirable.