Pulmonary gemcitabine delivery for treating lung cancer: pharmacokinetics and acute lung injury aspects in animals.
Gemcitabine, a nucleoside analogue for treating lung cancer, is clinically administered as an intravenous infusion. To achieve better patient compliance and more direct effect on the lung, we explored a new gemcitabine pulmonary delivery route and evaluated the pharmacokinetics and acute lung injury aspects in animals. Pharmacokinetics of gemcitabine were measured in Sprague-Dawley rats after intravenous (i.v.), intratracheal instillation by tracheotomy (i.t.t.), intratracheal instillation via orotrachea (i.t.o.), and intragastric (i.g.) administration of gemcitabine. Acute lung injury effects of the pulmonary delivery of gemcitabine were performed in Sprague-Dawley rats after i.t.o. and i.v. administration of gemcitabine and i.t.o. administration of lipopolysaccharide (LPS) as a positive control and physiological saline as a blank control. Indicators for acute lung injury that were evaluated included lung morphology, lung histopathology, lung coefficient, lung wet/dry weight ratio, total cell and classification counts in bronchoalveolar lavage cells (BALC), and total protein and TNF-alpha levels in bronchoalveolar lavage fluids (BALF). After i.t.t. or i.t.o. administration, gemcitabine was quickly absorbed, but i.g. administration led to an undetectable plasma gemcitabine concentration. Absolute bioavailability of gemcitabine after i.t.t. and i.t.o. administration was 91% and 65%, respectively. Gemcitabine given as i.t.o. administration did not cause any overt acute lung injury. All indicators for acute lung injury in the i.t.o. group were similar to those in the i.v. group or in the blank control, but significantly different from those in the positive control. In conclusion, the pharmacokinetics and acute lung injury studies suggest that pulmonary gemcitabine delivery would be a new and promising administration route.
Min
Rui
R
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing 100083, China.
Li
Ting
T
Du
Ju
J
Zhang
Yan
Y
Guo
Jia
J
Lu
Wan-Liang
WL
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000093542:Gemcitabine