Pharmacokinetics of intraperitoneal oxaliplatin: Experimental studies

Background and Objectives: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer . For cancers occurring within the abdominal cavity, the advantage of intra peritoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was desi gned to compare the pharmacokinetics and tissue absorption of intraperitone al versus intravenous oxaliplatin. Methods: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups accor ding to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraper itoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplati n (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At t he end of each procedure the animals were sacrificed. Selected tissue sampl es were taken in the second phase only. For all samples, platinum levels we re measured by direct current (d-c) plasma emission spectroscopy. Results: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal admi nistration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 ( +/- 5):1 for intraperitone al delivery as opposed to 1:5 ( +/- 2) for intravenous delivery (P = 0.0059 ). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 ( +/- 8 ):1. With the exception of the kidneys and the mesenteric nodes, tissue sam ples in the hyperthermic group exhibited increased oxaliplatin concentratio ns. These differences were not significant. For both groups colon tissues h ad the highest oxaliplatin concentrations. Conclusions: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal a dministration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxalipla tin for microscopic residual tumor after surgical resection of colon malign ancies. (C) 2001 Wiley-Liss, Inc.