title: Safety of pulmonary administration of gemcitabine in rats.
abstract: The purpose of this research was to evaluate the safety of pulmonary administration of gemcitabine and to determine the maximum tolerated dose by weekly pulmonary administrations in an animal model. Five groups of eight Wistar rats received gemcitabine at doses of 2, 4, 6, or 8 mg/kg or the vehicle solution by endotracheal spray with scintigraphic imaging of lung deposition. In order to document the safety of digestive exposure, five groups of eight rats received gemcitabine at the same dosages or the vehicle solution by gavage. Nine weekly sessions were planned, and blood cell counts and histological examinations were performed in live animals at day 64. Scintigraphic imaging confirmed pulmonary deposition in 310 of 316 spray administrations (98%) with homogeneous pattern of deposition. The maximum tolerated dose of gemcitabine by pulmonary administration was 4 mg/kg. At this dosage, administered once a week for 9 consecutive weeks, there were no chemotherapy-related deaths and no clinical, histological, or hematological signs of toxicity except for a decrease in platelet and red blood cell counts, with no clinical significance. The toxicity of gemcitabine was higher via oral than lung delivery in terms of weight loss and white blood cell toxicity at dosages of 2, 4, and 6 mg/kg. Pulmonary administration of gemcitabine is safe in rats at a maximum tolerated dose of 4 mg/kg once a week for 9 weeks. At an equivalent dosage, the toxicity of gemcitabine is lower by lung than oral administration.
authors.affiliation: Groupe de pneumologie, INSERM, U618, IFR135, Faculté de Médecine, Tours, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gagnadoux
authors.forename: Alain
authors.initials: A
authors.lastname: Le Pape
authors.forename: Thierry
authors.initials: T
authors.lastname: Urban
authors.forename: Jérome
authors.initials: J
authors.lastname: Montharu
authors.forename: Laurent
authors.initials: L
authors.lastname: Vecellio
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Dubus
authors.forename: Valérie
authors.initials: V
authors.lastname: Leblond
authors.forename: Patrice
authors.initials: P
authors.lastname: Diot
authors.forename: Daniel
authors.initials: D
authors.lastname: Grimbert
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Racineux
authors.forename: Etienne
authors.initials: E
authors.lastname: Lemarié
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005260:Female; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism*; D020714:Maximum Tolerated Dose; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine