Received for publication January 9, 2007.
Revised December 27, 2007.
Accepted for publication January 7, 2008.

Pharmacokinetics of Gemcitabine when delivered by Selective Pulmonary Artery Perfusion for the Treatment of Lung Cancer

Abstract

Lung cancer represents a major health problem. Cytostatic and radio-therapeutic treatment are both limited due to dose-limiting systemic toxicity and surgery due to its invasive nature. Therefore, we developed a catheterisation model of selective pulmonary artery perfusion (SPAP) combining the properties of isolated lung perfusion and intravenous treatment to achieve higher local drug levels and equivalent systemic exposure. Sixteen pigs underwent SPAP using a clinically applied dose of gemcitabine (1g/m²). They furthermore underwent thoracotomy for tissue sampling. Three groups were treated with SPAP for two minutes with normal pulmonary blood flow, 50% and 90% flow reduction. Another group had SPAP for ten minutes with normal blood flow. All SPAP groups underwent catheterisation of the left pulmonary artery. An additional group (n=4) was infused intravenously (IV) for thirty minutes using the same dose. Concentrations were analysed with ANOVA. Pulmonary peak concentrations (p=0.01) and areas under the curve (AUC) (p=0.001) of SPAP for two and ten minutes were significantly higher compared to IV while SPAP for ten minutes resulted in the highest AUC (p=0.045) compared to SPAP for two minutes. Flow reduction during SPAP resulted in inhomogeneous distribution. Liver levels, AUC (serum) and wet-to-dry ratios of all SPAP groups were not significantly different compared to IV. SPAP resulted in higher lung concentrations while systemic exposure was comparable with IV. Therefore, we advocate SPAP as a new method to be tested clinically to achieve down-staging of the tumour (T) and lymph node (N) status in lung cancer.

Key words: anticancer agents, clinical pharmacokinetics, drug distribution, drug transport, lung cancer, pharmacokinetics, pulmonary pharmacology