EXPERIMENTAL STUDY OF AORTIC STOP-FLOW INFUSION WITH HYPOXIC ABDOMINAL PERFUSION CHEMOTHERAPY

Abstract

We evaluated the pharmacokinetics of anticancer drugs, drug concentration in tissues of the liver and the pancreas, and the hematological changes in aortic stop-flow infusion with hypoxic abdominal perfusion (ASI with HAP) using Beagle dogs under general anesthesia.
Concerning the of blood concentrations of both mitomycin C (MMC) and 5-fluorouracil (5-FU), the area under the curve (AUC) with perfusion circuit (PC) in the ASI with HAP group was significantly higher than in the control group. On the contrary, there was no significant difference for AUC in the non-PC as compared with that in the control group. From these results, this method is effective to increase the blood concentration of drugs in target organs. It is suggested that the maximum dose of anticancer drugs in ASI with HAP should not greatly exceed the dose given in systemic administration by rapid intravenous injection.
Drug concentrations of both MMC and 5-FU in the ASI with HAP group were significantly higher than those in the control group in the liver and in the pancreas. Concentrations of MMC and 5-FU in hepatic tissue were lower than those in pancreatic tissue, and there was a tendency for the concentration in hepatic tissue to decline more rapidly in comparison of pancreatic tissue. This is ascribed to the fact that the catabolism of both agents occurs mainly in the liver.
The measurements of blood gas indicated that a hypoxic condition was maintained only in PC, and PC became lower in pH during perfusion. The results of blood biochemical examinations revealed that the variations in each parameter peaked between 15 and 30 minutes after completion of perfusion and that they all reached a plateau 60 minutes after completion. The increases of hepatic enzymes such as AST, ALT and LDH were ascribed to ischemia due to the aorta stop-flow and to the reperfusion injury of the liver following release of stop-flow. Superoxide dismutase (SOD) exhibited a sharp increase immediately after administration of anticancer drugs, which was ascribed to the influence of MMC administration. However, these biochemical changes in ASI with HAP were believed to be reversible and of short duration.