Role of retinal pigment epithelium permeability in drug transfer between posterior eye segment and systemic blood circulation

Abstract

Retinal pigment epithelium (RPE) is a major part of blood-retinal barrier that affects drug elimination from the vitreous to the blood and drug distribution from blood circulation into the eye. Even though drug clearance from the vitreous has been well studied, the role of RPE in the process has not been quantified. The aim of this work was to study the role of RPE clearance (CL_RPE) as part of drug elimination from the vitreous and ocular drug distribution from the systemic blood circulation. We determined the bidirectional permeability of eight small molecular weight drugs and bevacizumab antibody across isolated bovine RPE-choroid. Permeability of small molecules was 10^-6-10^-5 cm/s showing 13-15 fold range of outward and inward permeation, while permeability of bevacizumab was lower by 2-3 orders of magnitude. Most small molecular weight drugs showed comparable outward (vitreous-to-choroid) and inward (choroid-to-vitreous) permeability across the RPE-choroid, except ciprofloxacin and ketorolac that had an over 6 and 14-fold higher outward than inward permeability, respectively, possibly indicating active transport. Six of seven tested small molecular weight drugs had outward CL_RPE values that were comparable with their intravitreal clearance (CL_IVT) values (0.84-2.6 fold difference). On the contrary, bevacizumab had an outward CL_RPE that was only 3.5% of the CL_IVT, proving that its main route of elimination (after intravitreal injection) is not RPE permeation. Experimental values were used in pharmacokinetic simulations to assess the role of the RPE in drug transfer from the systemic blood circulation to the vitreous (CL_BV). We conclude that for small molecular weight drugs the RPE is an important route in drug transfer between the vitreal cavity and blood, whereas it effectively hinders the movement of bevacizumab from the vitreous to the systemic circulation.

Keywords: Blood-retina barrier; Bovine; Ex vivo; Intravitreal clearance; Ocular pharmacokinetics; Permeability; Retinal pigment epithelium.