Pharmacokinetics, pulmonary disposition and tolerability of liposomal gentamicin and free gentamicin in foals.

Abstract

Although gentamicin is highly active against Rhodococcus equi in vitro, its clinical efficacy has been limited presumably due to poor cellular uptake. Encapsulation of drugs in liposomes enhances their cellular uptake. 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. Experimental study. Eight healthy foals received a single i.v. or nebulised dose (6.6 mg/kg bwt) of LG or FG in a balanced Latin 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. 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. 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 Rhodococcus equi.