title: Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model.
abstract: Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 +/- 0.58 micro g/ml versus 0.14 +/- 0.04 and 0.11 +/- 0.09 micro g/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 +/- 0.21 micro g/ml) than after treatment with ABLC (0.27 +/- 0.18 micro g/ml) and D-AMB (0.16 +/- 0.04 micro g/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 +/- 0.43 micro g/ml) than after repeated doses of ABLC (0.03 +/- 0.02 micro g/ml) or D-AMB (0.13 +/- 0.06 micro g/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.
authors.affiliation: Department of Ophthalmology, University of Bern, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Goldblum
authors.forename: Kaspar
authors.initials: K
authors.lastname: Rohrer
authors.forename: Beatrice E
authors.initials: BE
authors.lastname: Frueh
authors.forename: Regula
authors.initials: R
authors.lastname: Theurillat
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Thormann
authors.forename: Stefan
authors.initials: S
authors.lastname: Zimmerli
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B