Pharmacokinetics and tissue uptake of mitomycin C in isolated perfusion of pancreas.

Isolated perfusion of organs or anatomic sites with chemotherapeutic agents offers a pharmacokinetic advantage of increasing drug bioavailability to target tissues which may result in a greater magnitude of biologic effect (pharmacologic or toxic) without systemic toxicity. Using a previously developed animal model, isolated perfusion (IP) of the canine pancreas-duodenum with incremental doses of mitomycin C (MMC) had shown a dose of 0.25 mg/kg body weight to be the maximum tolerable dose. The current study was designed to compare the pharmacologic advantage of drug delivery by IP by directly measuring tissue drug levels of radiolabeled MMC and comparing them with tissue levels attained by selective intraarterial (IA) and intravenous (IV) routes using identical doses of drug (n = 4 each). IP of pancreas-duodenum was performed for 45 min with a perfusate-to-systemic drug leak rate of less than 5%. IP was accomplished by using extracorporeal pump oxygenator at 39 degrees C and flow initiated at 110-120 ml/min, with a mean pressure of 90 mm Hg. Vascular inflow and outflow was isolated to the cannulated superior pancreaticoduodenal artery and vein. In the IA group drug was infused over 45 min through same artery as IP. IV group underwent identical dosing through the jugular vein. Direct measurement of drug in harvested pancreas and duodenum for each individual was done by tissue solubilization and scintillation assay. A 6-fold greater tissue level of drug in IP over IA and a 15-fold increase in IP over IV methods of delivery were found (P less than 0.01).