Intravitreal Pharmacokinetics of Plain and Liposome-Entrapped Fluconazole in Rabbit Eyes

Abstract

The objective of our experiment was to study the pharmacokinetics of plain and liposome-encapsulated fluconazole after an intravitreal injection (100 microg/0.1 ml) in rabbit eyes. Equal concentrations of plain and liposome-entrapped fluconazole were injected intravitreally into albino rabbits through the pars plana after intravenous pentobarbitone anesthesia. The rabbits were sacrificed at various time intervals, and the concentration of fluconazole in vitreous, retina-choroid, aqueous humor and cornea was estimated using High Performance Liquid Chromatography (HPLC). Plain fluconazole showed a rapid vitreal clearance and a short half-life (3.08 hr), whereas liposome-entrapped fluconazole showed a longer half-life (23.40 hr). The terminal elimination constant (Ke) of the liposome-loaded drug from the vitreous was seven times less than the plain drug. In the plain fluconazole group, at 1 hr, a high concentration of the drug was found in the retina. To conclude, the elimination of fluconazole was primarily transretinal and was very rapid. Liposome encapsulation significantly increased the half-life of fluconazole in the vitreous cavity.

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

“…Distribution depends on the ability of drug to partition into the tissues and it is described as volume of drug distribution. Drug elimination may take place posteriorly through the blood-retina barrier (Duvvuri et al, 2003;Gupta et al, 2000;Maurice and Mishima, 1984;Shen et al, 2007) to the choroidal blood circulation that constitutes most of the ocular blood flow (del Amo et al, 2015;Roh et al, 2006). Intravitreal drug is eliminated also anteriorly via aqueous humor turnover and uveal blood flow.…”

“…The importance of anterior and posterior routes depends on the drug properties (Maurice and Mishima, 1984): lipophilic drugs with high permeability in the blood-retina barrier are mostly eliminated posteriorly (e.g. fluconazole; vitreal clearance 0.753 ml/h (Gupta et al, 2000)), whereas elimination of large and hydrophilic compounds is restricted to the anterior route (e.g. bevacizumab; vitreal clearance 0.019 ml/h (Bakri et al, 2007;Christoforidis et al, 2011;del Amo et al, 2015)).…”

The Antiangiogenic Effects of Gold Nanoparticles on Experimental Choroidal Neovascularization in Mice

“…Nanoparticles are generally considered to be able to avoid the quick clearance and improve retention in the vitreous and the retina compared with large molecules. [24][25][26][27] The larger molecules are cleared from the vitreous body by the circulation and vitreous turnover, resulting in short intraocular half-life. Particle size-dependent ocular distribution and half-life were investigated in rabbits by Sakurai et al 28 The 2-lm particles (t 1/2 ¼ 5.4 days) were detected near trabecular meshwork where they were drained out, whereas the 200-nm particles (t 1/2 ¼ 8.6 days) were evenly distributed in the vitreous cavity, and the 50-nm particles (t 1/2 ¼ 10.1 days) crossed the retina and were found to remain in the retina even after 2 months.…”

Ocular drug delivery systems: An overview

“…For posterior segment delivery, liposomes development is more focused toward improving half-life of drug by lessening clearance from vitreous humor, protecting labile molecules such as peptides and oligonucleotides from degradation and providing sustained drug release [5,85,86] . For instance, the vitreal half-life of fluconazole in rabbit eye was increased from 3.08 to 23.40 h after formulating into liposomes [86] .…”