OBJECTIVE: To determine the pharmacokinetics and efficacy of tobramycin against pulmonary infections of Pseudomonas aeruginosa in rats after intratracheal administration of conventional and liposomal formulations. METHODS: Male Sprague-Dawley rats were inoculated with 10(6) cfu of a mucoid variant of P. aeruginosa (MIC of tobramycin for PA 508 = 1 mg/l) and tobramycin (conventional or liposomal formulations) was administered in single (490 microg) and multiple dose (490 microg during 4 days) experiments. Rats were killed at multiple time points to determine the residual cfu of P. aeruginosa and tobramycin amounts in lungs. Pharmacokinetic parameters were calculated using a two-compartment model with NONMEM. RESULTS: Mean (+/-S.D.) elimination half-life (t(1/2beta)) and pulmonary exposure (AUC) of the conventional formulation were 14.0 +/-4.0 h and 663 +/-89 microg x h/lungs, respectively. The pharmacokinetic profile of liposomal tobramycin was markedly different, with a longer t(1/2beta) (34.4 +/-5 h, P < 0.05), resulting in an increased AUC (3890 +/-560 microg x h/lungs, P < 0.05). chi(2) analyses were carried out on cfu data distributed in the following categories: below 10(3), 10(3)-10(5), and above 10(5) cfu. In the single dose experiments, approximately 90% of the observations were above 10(5) cfu for both formulations. Significant differences in cfu distribution were observed after multiple treatments, with approximately 10% of the observations falling below 10(3) cfu of P. aeruginosa for the conventional formulation versus 30% for the liposomal formulation. CONCLUSION: The liposomal formulation of tobramycin promoted drug retention in lungs and improved its efficacy after multiple treatments.
OBJECTIVE: To determine the pharmacokinetics and efficacy of tobramycin against pulmonary infections of Pseudomonas aeruginosa in rats after intratracheal administration of conventional and liposomal formulations. METHODS: Male Sprague-Dawley rats were inoculated with 10(6) cfu of a mucoid variant of P. aeruginosa (MIC of tobramycin for PA 508 = 1 mg/l) and tobramycin (conventional or liposomal formulations) was administered in single (490 microg) and multiple dose (490 microg during 4 days) experiments. Rats were killed at multiple time points to determine the residual cfu of P. aeruginosa and tobramycin amounts in lungs. Pharmacokinetic parameters were calculated using a two-compartment model with NONMEM. RESULTS: Mean (+/-S.D.) elimination half-life (t(1/2beta)) and pulmonary exposure (AUC) of the conventional formulation were 14.0 +/-4.0 h and 663 +/-89 microg x h/lungs, respectively. The pharmacokinetic profile of liposomal tobramycin was markedly different, with a longer t(1/2beta) (34.4 +/-5 h, P < 0.05), resulting in an increased AUC (3890 +/-560 microg x h/lungs, P < 0.05). chi(2) analyses were carried out on cfu data distributed in the following categories: below 10(3), 10(3)-10(5), and above 10(5) cfu. In the single dose experiments, approximately 90% of the observations were above 10(5) cfu for both formulations. Significant differences in cfu distribution were observed after multiple treatments, with approximately 10% of the observations falling below 10(3) cfu of P. aeruginosa for the conventional formulation versus 30% for the liposomal formulation. CONCLUSION: The liposomal formulation of tobramycin promoted drug retention in lungs and improved its efficacy after multiple treatments.
Authors: Jae-Ho Lee; Kenneth T Cheng; Vladimir Malinin; Zhili Li; Zhengsheng Yao; Sung-Jin Lee; Christine M Gould; Kenneth N Olivier; Clara Chen; Walter R Perkins; Chang H Paik Journal: J Liposome Res Date: 2013-07-24 Impact factor: 3.648
Authors: Khadijah M Hindi; Andrew J Ditto; Matthew J Panzner; Douglas A Medvetz; Daniel S Han; Christine E Hovis; Julia K Hilliard; Jane B Taylor; Yang H Yun; Carolyn L Cannon; Wiley J Youngs Journal: Biomaterials Date: 2009-04-23 Impact factor: 12.479
Authors: Ryan A Orizondo; Charlene Irvin Babcock; Mario L Fabiilli; Leonid Pavlovsky; J Brian Fowlkes; John G Younger; Keith E Cook Journal: J Aerosol Med Pulm Drug Deliv Date: 2014-01-29 Impact factor: 2.849