Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles.
The inhalation delivery of 5-fluorouracil (5-FU) in lipid-coated nanoparticles (LNPs) to hamsters was evaluated to determine the feasibility for use in lung cancer chemotherapy. The inhaled dose, 30 mg LNPs/kg body weight (1.5 mg/kg 5-FU), was delivered over an 8-min interval. Fluorescein isothiocyanate dextran (FITC-dextran) was included within the LNPs to provide an estimate of the particle concentration. The concentration of FITC-dextran and total 5-FU (released and LNP-associated) was determined as a function of time in the lung, trachea, larynx, esophagus, and serum. Concentrations of 5-FU and FITC-dextran were initially high in the trachea, larynx, and esophagus, and lower in the lung. Within 24 h, greater than 99% of the LNPs were cleared from the respiratory tract and total 5-FU concentrations mirrored the LNP concentration. An eight-compartment pharmacokinetic model was used to describe the observed trends in concentrations of LNPs and total 5-FU and to estimate the released 5-FU concentration in the above tissues. From this analysis, effective local targeting as well as sustained efficacious concentrations of 5-FU in the expected tumor sites were demonstrated.
Hitzman
Cory J
CJ
Department of Pharmaceutics, University of Minnesota, College of Pharmacy, Minneapolis, MN 55455, USA.
Wattenberg
Lee W
LW
Wiedmann
Timothy S
TS
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D006224:Cricetinae; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000737:chemistry; D005240:Feasibility Studies; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005472:Fluorouracil / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008647:Mesocricetus; D010316:Particle Size; D014018:Tissue Distribution
D000336:Aerosols; D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D003911:Dextrans; D005456:Fluorescent Dyes; D008055:Lipids; D016650:Fluorescein-5-isothiocyanate; D005472:Fluorouracil