Liquid dose pulmonary instillation of gentamicin PulmoSpheres formulations: tissue distribution and pharmacokinetics in rabbits.
OBJECTIVE
To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle.


METHODS
Rabbits were anesthetized, intubated, and mechanically ventilated with O2 (FiO2 = 0.50). Animals were then given 5 mg/kg gentamicin either intravenously, intramuscularly (TM), or intratracheally (IT) gentamicin PulmoSpheres formulation, instilled in 1.8 ml/kg of liquid perflubron vehicle. Serum and lung lobe sections were collected at multiple time points and assayed for gentamicin content.


RESULTS
Serum gentamicin levels peaked at 64.7 microg/ml, 11.2 microg/ml, and 5.0 microg/ml following intravenous, TM, and IT administration, respectively. Absolute bioavailabilitv at 8 h for IM administration was 76.8% and 57.0% when delivered IT. Although peak lung levels of drug were reached within 1 h, total lung gentamicin concentration after IT administration was more than two orders of magnitude greater than that achieved following TM administration (680,540 vs. 4,985 microg min, respectively) with significant levels of the antibiotic remaining in the lung even after 1 week.


CONCLUSIONS
High levels of gentamicin in lung tissue can be achieved by instillation of a gentamicin PulmoSpheres formulation in a perflubron vehicle, termed liquid dose installation, without reaching toxic systemic levels allowing for increased local delivery of agents such as gentamicin at the site of the infection.
Smith
D J
DJ
Alliance Pharmaceutical Corporation, San Diego, California 92122, USA. djs@allp.com
Gambone
L M
LM
Tarara
T
T
Meays
D R
DR
Dellamary
L A
LA
Woods
C M
CM
Weers
J
J
D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001681:Biological Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005079:Excipients; D005466:Fluorocarbons; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006842:Hydrocarbons, Brominated; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008863:Microspheres; D019999:Pharmaceutical Solutions; D011817:Rabbits; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D005079:Excipients; D005466:Fluorocarbons; D005839:Gentamicins; D006842:Hydrocarbons, Brominated; D019999:Pharmaceutical Solutions; C003072:perflubron