Pharmacokinetics after pulmonary artery perfusion with gemcitabine.
BACKGROUND
Isolated lung perfusion (ILuP) proved to be superior for the treatment of lung metastases compared with intravenous (i.v.) 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 i.v.. 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 microg/mL, 7.2 microg/mL, and 2.2 microg/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 i.v. 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 i.v. injection was higher compared with BFO but did not result in higher lung levels.
Van Putte
Bart P
BP
Department of Thoracic and Vascular Surgery, University Hospital, Antwerp, Edegem, Belgium.
Hendriks
Jeroen M H
JM
Romijn
Sander
S
Pauwels
Bea
B
De Boeck
Gert
G
Guetens
Gunther
G
De Bruijn
Ernst
E
Van Schil
Paul E Y
PE
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D011652:Pulmonary Circulation; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine