Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques

Objective: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. Methods: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. Results: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5-to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. Conclusions: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.