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Pharmacokinetics, pulmonary disposition and tolerability of liposomal gentamicin and free gentamicin in foals
Author(s) -
Burton A. J.,
Giguère S.,
Arnold R. D.
Publication year - 2015
Publication title -
equine veterinary journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.82
H-Index - 87
eISSN - 2042-3306
pISSN - 0425-1644
DOI - 10.1111/evj.12309
Subject(s) - gentamicin , pharmacokinetics , tolerability , volume of distribution , medicine , aminoglycoside , pharmacology , bronchoalveolar lavage , bioavailability , horse , creatinine , chemistry , antibiotics , adverse effect , lung , biology , biochemistry , paleontology
Summary Reasons for performing the study Although gentamicin is highly active against R hodococcus equi in vitro , its clinical efficacy has been limited presumably due to poor cellular uptake. Encapsulation of drugs in liposomes enhances their cellular uptake. Objectives To compare the disposition of liposomal gentamicin ( LG ) and free gentamicin ( FG ) in the plasma, pulmonary epithelial lining fluid and bronchoalveolar cells of healthy foals after i.v. administration or by nebulisation, and to assess the tolerability of the drug after repeated i.v. dosing. Study design Experimental study. Methods Eight healthy foals received a single i.v. or nebulised dose (6.6 mg/kg bwt) of LG or FG in a balanced L atin square design, with a 14‐day washout period between treatments. Subsequently, 12 healthy foals were given either LG or FG at 6.6 mg/kg bwt i.v. q. 24 h for 7 doses and urinary protein, creatinine, γ‐glutamyltransferase and electrolytes were measured on Days 0, 3 and 7 to quantify renal injury. Concentrations of gentamicin were measured using liquid chromatography‐tandem mass spectrometry. Results After i.v. administration, LG had a significantly higher mean (± s.d.) half‐life (16.3 ± 3.5 vs. 6.2 ± 1.8 h) and volume of distribution (2.00 ± 1.03 vs. 0.72 ± 0.32 l/kg bwt) compared with FG . Peak gentamicin concentrations in bronchoalveolar cells were significantly higher for LG compared with FG after administration by both the i.v. (5.27 ± 2.67 vs. 2.98 ± 1.67 mg/l) and the nebulised (4.47 ± 2.66 vs. 1.49 ± 0.57 mg/l) routes. Liposomal gentamicin was well tolerated by all foals and indices of renal injury were not significantly different from those of foals administered FG . Conclusions Administration of LG is well tolerated and results in higher intracellular drug concentrations than FG . Liposomal gentamicin warrants further investigation for the treatment of infections caused by intracellular pathogens such as R hodococcus equi .