Pharmacokinetics of Isolated Hepatic Perfusion with High Dose Tumor Necrosis Factor in Rat Model

Background: Although the application of an isolation procedure with tumor necrosis factor (TNF) to the liver is quite attractive, an animal model is not yet available to evaluate antitumor effects by TNF in isolated hepatic perfusion (IHP). To establish the rat model in IHP, the pharmacokinetics of TNF, both in a perfusate and in a systemic circuit should be examined.

Methods: All rats underwent IHP with TNF. After a 10 min perfusion, a washout procedure was performed for 5 min, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the systemic blood and concentrations of TNF were assayed by L-929 cytotoxicity.

Results: After the administration of 240 micrograms of TNF in the circuit, TNF reached a plateau at about 12.7 micrograms/ml of perfusion fluid, lasting until the end of IHP. As a result of the washout procedure, regional TNF concentrations declined from 12.7 micrograms/ml to 1.5 micrograms/ml. At the beginning of the IHP, all rats exhibited no detectable level of TNF activity in the systemic circulation (< 100 pg/ml). With time, TNF plasma levels quickly increased to reach a plateau of about 0.2 microgram/ml at 15 min. Systemic leakage of TNF is calculated as less than 2% of the total TNF in perfusate during perfusion.

Conclusion: Rat IHP models with TNF showed that systemic leakage of TNF was higher than that of pig models, although a large enough amount of TNF in perfusate was achieved without death. Rat models might be feasible to evaluate antitumor effect of IHP against liver metastatic tumors.