Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles

J Pharm Sci. 2006 Jun;95(6):1196-211. doi: 10.1002/jps.20607.

Abstract

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.

MeSH terms

  • Administration, Inhalation
  • Aerosols
  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / chemistry
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Carcinoma, Squamous Cell / drug therapy
  • Cricetinae
  • Delayed-Action Preparations
  • Dextrans / chemistry
  • Feasibility Studies
  • Fluorescein-5-isothiocyanate
  • Fluorescent Dyes
  • Fluorouracil / administration & dosage
  • Fluorouracil / chemistry
  • Fluorouracil / pharmacokinetics*
  • Lipids / chemistry
  • Lung Neoplasms / drug therapy
  • Male
  • Mesocricetus
  • Particle Size
  • Tissue Distribution

Substances

  • Aerosols
  • Antimetabolites, Antineoplastic
  • Delayed-Action Preparations
  • Dextrans
  • Fluorescent Dyes
  • Lipids
  • Fluorescein-5-isothiocyanate
  • Fluorouracil