Pharmacokinetic studies of intraaortic stop-flow infusion with 14C-labeled mitomycin C

Abstract

This pharmacokinetic study attempted to improve the exposure of gastrointestinal tract tissues to chemotherapy by increasing the transit time of a first pass of a drug through the vascular system. Bolus infusion of 9 mg mitomycin (MMC) mixed with 1 mg of MMC labeled by 50 microCi of 14C was performed in 18 mongrel dogs. Pharmacokinetics of MMC in peripheral, portal, and aortic blood were studied under different types of major vessel occlusion. Three dogs with intravenous infusion constituted a control group. In 15 dogs MMC was infused intraaortically with the catheter's tip at the level of the celiac and superior mesenteric artery. Vascular flow was controlled in four different ways for 30 min: Type I-Type IV. In Type IV the abdominal aorta and vena cava inferior were occluded after surgical exclusion of all nongastrointestinal branches of aorta. Blood samples were obtained during a 90-min period. After solubilizing the samples, 14C-labeled MMC activity was counted by a scintillation counter. For stop-flow infusion Type I, II, III, and IV, area under the curve (AUC) ratios for portal blood versus systemic circulation were 1.6:1, 2.9:1, 2.9:1, and 8.8:1, respectively (statistically significant for Types II, III, and IV). The highest value of AUC, peak MMC concentration, and lowest clearance in portal blood were achieved in SFI Type IV. Exposure to MMC was the greatest with SFI Type IV, making this type of aortic stop-flow infusion the most favorable mode of drug administration from a pharmacokinetic perspective.