The impact of active transport on rabbit corneal drug permeability: utilizing the microflow-based PermeaSys device

Transcorneal permeation is the main entry route into the eye for topically applied drugs, but the impact of active transport on corneal permeability is still poorly understood. We aimed to identify the influence of transporters for rabbit corneal permeability by utilizing the PermeaSys microfluidic system, which requires <20 times smaller tissue pieces and 10 times smaller exposure volumes of the study compound, than the commonly used Ussing chamber. The rabbit corneal permeability was first validated with three model compounds, rhodamine 123, benzoic acid, and paracellular marker compound lucifer yellow, before studying the permeability with three clinically used drugs, ciprofloxacin, diclofenac, and methotrexate. Both bidirectional and inhibition studies were performed. Rhodamine 123 did not show directionality nor altered permeability in the presence of an inhibitor, but the permeability of benzoic acid was affected by a monocarboxylate transporter inhibitor, valproic acid. Clinically used compounds ciprofloxacin, diclofenac, and methotrexate did not show directionality in the corneal permeability studies. However, methotrexate permeability was altered when administered together with sulfasalazine and MK-571, which can inhibit several known drug transporters. The data generated here with the PermeaSys instrument is comparable to studies conducted with the Ussing chamber, indicating that it can be reliably used for the study of permeability and active transport in the cornea. However, active transport does not appear to have a great impact on the corneal permeability of the studied drug compounds.