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Ann Thorac Surg 2003;76:1036-1040
© 2003 The Society of Thoracic Surgeons

Original article: general thoracic

Pharmacokinetics after pulmonary artery perfusion with gemcitabine

Bart P. Van Putte, MDa, Jeroen M. H. Hendriks, MD, PhDa*, Sander Romijn, MDa, Bea Pauwelsb, Gert De Boeck, PharmDb, Gunther Guetens, PharmDc, Ernst De Bruijn, PharmDc, Paul E. Y. Van Schil, MD, PhDa

a department of Thoracic and Vascular Surgery, University Hospital, Antwerp, Edegem, Belgium
b department of Medical Oncology, University Hospital, Antwerp, Edegem, Belgium
c Department of Oncology and Radiotherapy, Catholic University of Leuven, Leuven, Belgium

* Address reprint requests to Dr Hendriks, Department of Thoracic and Vascular Surgery, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem (Antwerp), Belgium.
e-mail: jeroen.hendriks{at}uza.be

Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 
BACKGROUND: Isolated lung perfusion (ILuP) proved to be superior for the treatment of lung metastases compared with intravenous (IV) injection. However its invasive character limits repetitive treatment. Blood flow occlusion (BFO) as a regional therapy with gemcitabine (GCB) was evaluated in a rat model. Lung levels of GCB were examined with different exposure times and flow rates and compared with ILuP and IV. Cell kill was studied in vitro.

METHODS: In vitro survival of CC531 adenocarcinoma cells was determined after 10, 20, and 40 minutes of exposure to GCB. In vivo 48 Wag/Rij rats underwent BFO with GCB at a rate of 0.2 mL/min and 0.5 mL/min during 10, 20, 30, and 40 minutes. Statistical analysis was performed using Student's t test.

RESULTS: In vitro, the dose of GCB resulting in 50% growth inhibition was 9.1 µg/mL, 7.2 µg/mL, and 2.2 µg/mL after 10, 20, and 40 minutes exposure respectively. In vivo, no significant difference in lung levels of GCB was observed between a flow rate of 0.2 mL/min compared with 0.5 mL/min at any exposure time point (p < 0.05). Lung tissue was saturated after 20 minutes. Blood flow occlusion resulted in a lower plasma levels and higher lung levels of GCB compared with IV injection of the maximal tolerated dose of 40 mg.

CONCLUSIONS: Growth inhibition of CC531 cells in vitro increased with exposure time while lung tissue was saturated after 20 minutes of BFO. No difference in GCB lung levels were seen after BFO compared with ILuP. Systemic exposure after IV injection was higher compared with BFO but did not result in higher lung levels.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 
Isolated lung perfusion is an experimental surgical procedure for the treatment of pulmonary metastatic disease in order to improve the current 5-year survival rate of approximately 40% after resection of lung metastases [1]. The aim of this technique is to achieve high local lung concentrations without systemic exposure. It can be a treatment option to make bulky metastatic disease operable or to prevent intrathoracic recurrences after removal of macroscopic metastatic disease of the lung. Although the procedure itself is well tolerated [2] it is a highly invasive procedure unlikely to be performed more than once. Therefore regional infusion techniques like bronchial artery infusion or pulmonary artery perfusion without control of the venous circulation are preferred because these procedures can be repeated in time [3, 4]. Only drugs with a good first-pass effect can be selected since systemic exposure must be limited to a minimum. Gemcitabine (GCB) given by isolated lung perfusion proved to be well tolerated while demonstrating a good first-pass effect within the lung [5]. Therefore GCB was selected as the agent of choice for the present study, which evaluated the in vitro toxicity of gemcitabine in an adenocarcinoma cell line and the lung and serum levels of gemcitabine (GCB) during perfusion of the pulmonary artery.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 Discussion
 References
 
Animals
Male inbred WAG-Rij strain rats (weight, approximately 225 g) obtained from Iffa Credo (Brussels, Belgium) were used for all experiments. Animals were treated in accordance with the Animal Welfare Act and the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health Publication 86-23, revised 1985). The rats were transported in sterile conditions, housed in suspended mesh wired cages, and fed a standard pellet diet ad libitum (standard rat chow; Hope Farms, Woerden, The Netherlands). The experimental protocols were approved by the Institutional Animal Care and Use Committee, University Hospital of Antwerp.

Cell line
The CC531 second tumor cell line was used in this study to determine the sensitivity for the cytotoxic effect of gemcitabine. This cell line was derived from a chemically induced adenocarcinoma of the colon of a WAG rat [6].

The CC531 second tumor cell line was cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (Invitrogen, Merelbeke, Belgium). Cultures were maintained in exponential growth in a humidified atmosphere at 37°C, less than 5% CO2 and 95% air.

Pulmonary artery perfusion
Pulmonary artery perfusion is performed as an isolated left lung perfusion procedure without venous control [7]. Briefly, anesthesia was induced with isoflurane in a mixture of nitrous oxide (N2O) and oxygen (O2). Isoflurane was administered in a concentration of 4%; N2O:O2 ratio was 3:1. Next, rats were intubated by translaryngeal illumination and connected to a volume-controlled ventilator at a rate of 75 strokes/min and a tidal volume of 10 mL/kg. After a left thoracotomy the pulmonary artery was clamped with a curved microclip. A PE-10 perfusion catheter was introduced into the pulmonary artery. Before starting perfusion the position of the tip of the catheter was checked to prevent selective perfusion of one part of the left lung. Perfusate was delivered through this catheter at a chosen rate. At the completion of lung perfusion the rat was killed by a venous cut down the caval vein.

The perfusate was temperature controlled at 37°C throughout the whole perfusion. Rats were placed on a heating pad immediately after induction and body temperature was kept constantly between 34°C and 37°C.

Gemcitabine processing and measurement
Gemcitabine (difluorodeoxycytidine; Ely Lilly Benelux, Brussels, Belgium) perfusate solutions were prepared by reconstituting nonlyophilized powder in the supplied diluent and performing appropriate dilutions with BHE before the experiments.

A high-performance liquid chromatographic (HPLC) method was used for measuring gemcitabine levels in lung tissue and serum. Deoxycytidine was used as an internal standard. Samples were extracted over a Chrompack Spherisorb ODS-2 reversed phase column [8, 9].

Experiment 1: cell survival after treatment with gemcitabine
Cells were harvested from exponential phase cultures by trypsinization, counted, and plated in 48-wells plates. In order to assure exponential growth during the experiments seeding density was 1.000 cells per well. After plating and a 24-hour recovery period cells were treated with gemcitabine (0, 10, 20, and 40 µmol/L) dissolved in phosphate buffered saline (PBS) for 10, 20, or 40 minutes. Phosphate buffered saline was added to control cells. Each concentration was tested in sextuple within the same experiment. After incubation with gemcitabine, cells were washed with drug free medium. Four days after treatment the survival was determined by the sulforhodamine B (SRB) assay, which was performed according to the method of Skehan [10] and Papazisis [11].

The survival rates were calculated as follows: mean OD (optical density) of treated cells/mean OD of control cells x 100%. The dose response curves were fitted to the sigmoid inhibition model: E(survival) = 1 -(C{gamma}/C{gamma}+IC50{gamma}), using Winnonlin (Pharsight, Palo Alto, CA) to calculate the values for the concentration of gemcitabine causing 50% growth inhibition (IC50).

Experiments were performed at least three times. All data are presented as the mean ± SD.

Experiment 2: pulmonary artery perfusion
Forty-eight Wag/Rij rats underwent pulmonary artery perfusion. These rats were randomly assigned into eight groups of 6 rats each. Gemcitabine was given at a concentration of 2.7 mg/mL during 10, 20, 30, and 40 minutes respectively. Half of the groups was perfused at a rate of 0.5 mL/min while the others were perfused at 0.2 mL/min. At the end of the procedure the lung was removed for determination of the wet-to-dry ratio and analysis of GCB levels. Lung biopsies were taken at the lateral side of the lung, both in the proximal and distal half. In 6 rats in the group with a flow rate of 0.2 mL/min serum samples were collected at 20 and 30 minutes for later analysis of serum GCB levels.

Ten rats received the maximum tolerated intravenous dose of GCB, 160 mg/kg (40 mg per rat). Serum samples were collected at 6, 12, 15, and 21 minutes and stored at -70°C for measurement of GCB lung and serum levels.

Statistical analysis
All data are presented as mean ± SD. Data were analyzed using Student's t test. Significance was defined as p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 Discussion
 References
 
Experiment 1
The dose-response curve is shown in Figure 1. The IC50 value of CC531 for gemcitabine at 10 minutes is 9 µg/mL, at 20 minutes 7.2 µg/mL, and at 40 minutes 2.2 µg/mL.



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  		Fig 1. Mean surviving fraction of CC531 colonies measured as a function of gemcitabine (GCB) concentration. Exposure times are 10 minutes (dashes), 20 minutes (diamonds), and 40 minutes (squares).

 
Experiment 2
Lung levels of GCB stabilized after 10 minutes for a infusion rate of 0.5 mL/min, and after 20 minutes for a rate of 0.2 mL/min (Table 1 . and Fig 2). No difference in lung levels of GCB is seen at different times between the two flow rates (Table 2).


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  		Table 1. Dose and Concentration of Gemcitabine Delivered by Blood Flow Occlusion

 


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  		Fig 2. Gemcitabine (GCB) lung levels as function of exposure time. Triangles = 0.2 mL/min; squares = 0.5 mL/min.

 

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  		Table 2. Gemcitabine Lung Levels After Blood Flow Occlusion

 
No significant difference in wet-to-dry ratio was measured between both flow groups or between different perfusion times (Fig 3).



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  		Fig 3. Wet-to-dry ratio as a function of perfusion time and flow rate. Open bars = 0.5 mL/min; solid bars = 0.2 mL/min.

 
No significant difference in serum levels of GCB was observed after intravenous infusion in time (Fig 4, upper curve). Serum levels during left lung perfusion at 0.2 mL/min (Fig 4, lower curve) were significantly lower (p = 0.02) while lung levels were significantly higher (p = 0.003) compared with intravenous infusion (0.2 µg/g) [11].



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  		Fig 4. Gemcitabine (GCB) serum levels after intravenous (IV [squares]) infusion and blood flow occlusion (BFO [triangles]).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 Discussion
 References
 
Complete surgical resection of pulmonary metastatic disease results in a 5-year survival of approximately 40% [1]. Different novel target techniques to achieve a higher local drug concentration in the lung are explored in an attempt to improve this survival [12]. Isolated lung perfusion as a surgical technique was already described in 1959 by Creech [13] to obtain high lung levels without systemic exposure. In addition it avoids metabolisation by the liver or kidney. The technique was reinvented by the group of Johnston [2] during the 1980s and tested in large animals by several investigators [2, 14–16]. The lung proved to be an ideal organ since a complete vascular isolation was possible without systemic exposure. The lung could also tolerate temperatures as high as 44°C. Next with the development of rat models of ILuP, several drugs were tested for their tumor efficacy. All these experiments showed IluP to be superior to intravenous infusion, both pharmacokinetically and therapeutically as well [17–21]. These findings resulted in some phase I trials of ILuP with different agents, some of them already finished [22–25].

The main disadvantage of the technique of ILuP is its invasive character. It necessitates a thoracotomy while its effect has to be exerted during a single procedure. Therefore it is doubtful that ILuP becomes useful to treat bulky metastatic disease or to make inoperable patients curable. Regional infusion techniques such as bronchial artery infusion or pulmonary artery perfusion have the advantage that they can be repeated but drugs need to have a good first-pass effect in order to minimize systemic leakage through an open venous circulation. Since lung metastases are mainly supplied by the pulmonary artery, pulmonary artery perfusion by endovascular way is the preferred technique. Of these techniques blood flow occlusion (BFO) as described by Wang [4] proved to be superior and has been tested with success for doxorubicin [4, 26].

The aim of this study was to assess the use of gemcitabine by BFO and compare it with ILuP, which was tested in a previous experiment [5]. As a first step the IC50 of gemcitabine was explored for an adenocarcinoma cell line of which a rat model of pulmonary metastatic disease is present at our laboratory [20]. These in vitro experiments showed that 50% of the cells were killed between a concentration of at least 2.2 mg/mL for 40 minutes and 7.2 mg/mL for 20 minutes. In a next experiment plasma and lung concentrations were compared among BFO, IV injection, and ILuP. The concentrations after ILuP were extrapolated from a previous experiment. Isolated lung perfusion with 40 mg (160 mg/kg) resulted in lung levels of 1.5 µg/g of GCB [5]. The flow rate of 0.5 mL/min used for the ILuP experiments was chosen for the BFO as well. In addition a lower perfusion rate (0.2 mL/min) was selected in order to reduce the total amount of drug given for the same perfusion time (Table 2). The concentration of GCB within the perfusate was the same for all BFO groups. For the intravenously treated animals the maximum tolerated dose of 160 mg/kg was given. In this way maximum systemic exposure achieving the highest lung levels after intravenous injection were compared with regional techniques such as ILuP and BFO. Although the same concentration was delivered by BFO in all groups the rate of 0.2 mL/min resulted in the same final lung levels compared with 0.5 mL/min for all groups, whereas the total amount of GCB given was only half. Although the total dose of GCB after intravenous injection (40 mg, the maximal tolerated dose) was significantly higher compared with BFO at a rate of 0.2 mL/min, lung levels after intravenous injection were significantly lower (0.2 µg/g) compared with BFO but serum levels were higher. Gemcitabine lung levels of 1.5 µg/g after ILuP for 30 minutes with a dose of 40 mg were not significantly different from BFO at the lowest rate for 20, 30, and 40 minutes. However the total amount of GCB given was less compared with ILuP.

In conclusion our experiments demonstrate that the same gemcitabine levels in lung tissue can be obtained using ILuP or BFO. Compared with IV drug administration the plasma levels are lower while the lung tissue concentrations are higher with BFO. Compared with ILuP a higher and nontoxic systemic exposure is present after BFO while no different lung levels are seen for a lower total amount of GCB given. In addition BFO is technically less demanding and can be used clinically by catheterization of the pulmonary artery.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
Discussion
 References
 
The authors thank A. Van Laer for technical assistance during all experiments and Eli Lilly for providing gemcitabine.


   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
References
 
DR W. ROY SMYTHE (Houston, TX): Does it make any difference if you oxygenate the perfusate in these animals? Clinically one of the problems that has been seen with isolated lung perfusion when the lung is not being ventilated and the circuit is not oxygenated is an acute lung injury, one that appears to be out of proportion with what you would expect from the chemotherapeutic agent alone.

Second, does it make any difference if you inflate the lung during perfusion? We know from lung transplantation that if you want to perfuse the entire lung with your preservative that not only do you give a vasodilator but you also inflate the lung to eliminate the peripheral pulmonary vasoconstriction.

I wondered if those two things make any difference, if you had planned experiments in that regard, or if you were going to apply that clinically.

DR FRANK A. BACIEWICZ (Detroit, MI): I have just one question. How did you decide on what concentration of the chemotherapeutic agent to use in the lung? Was that arbitrary or was that previous research?

DR TIMOTHY M. ANDERSON (Buffalo, NY): You are investigating the concentration levels of gemcitabine in lung and state this chemotherapeutic agent might hold promise for future clinical applications. At Roswell Park we are utilizing combination gemcitabine and navelbine in a neoadjuvant setting for early stage lung cancer. Both on and off protocol we have experienced gemcitabine pulmonary toxicity, in particular affecting the diffusion capacity at up to 3 weeks after cessation of the drug. Hence, we have delayed surgery until 4 weeks after discontinuing chemotherapy. Have you allowed any of these rats to live after chemoperfusion to assess the postoperative clinical effects of gemcitabine?

DR VAN PUTTE: Regarding the first two questions. During all perfusions both lungs were inflated with a mixture of oxygen, nitrous oxide, and isoflurane while the perfusate was not oxygenated. The perfused lung was ventilated in order to prevent peripheral vasoconstriction as Dr Smythe already pointed out. It is clear that vasoconstiction will diminish the uptake of the drug into the lung. Lung injury as a result of isolated lung perfusion itself was not studied here. However, we recently investigated lung injury and cells infiltrating the lung after warm pulmonary ischemia-reperfusion. After 1 hour of warm ischemia followed by 4 hours of reperfusion a significant increase in number of apoptotic cells was observed in total absence of necrosis.

Regarding the third question, in a former study that is in press in the Journal of Surgical Research, we concluded that 160 mg/kg of gemcitabine is the maximum tolerated dose intravenously while the maximum tolerated dose during isolated lung perfusion was 320 mg/kg. We finally chose 160 mg/kg in this study because we wanted to compare the effects of low-flow selective pulmonary artery perfusion with intravenous infusion.

Regarding the fourth question, in a recent study we investigated long-term histologic side effects after isolated lung perfusion using gemcitabine in a dose-escalating schedule. No major fibrotic changes could be observed in the perfused lungs treated with doses up to 320 mg/kg. Only slight fibrotic changes in the alveolar septa correlating with pleural fibrosis could be observed. A study of functional changes in lung capacity after isolated lung perfusion is planned for the near future. Thank you.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 

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