Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine

Abstract

Purpose. The objective of this study was to determine the effect of the multi-drug efflux transport protein, P-glycoprotein (P-gp), on the ocular distribution of a model substrate, quinidine. Methods. Male New Zealand albino rabbits (2–2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5mg/kg bodyweight) and intravitreally (5.68µg and 0.568µg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. Results. Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 ± 6.47 min.µg/ml), maximum concentration achieved (C max) (0.095 ± 0.011µg/ml), vitreal elimination half-life (231.96 ± 10.77 min), vitreal permeation half-life (16.57 ± 6.96 min) were significantly different from the control values (19.21 ± 3.73 min.µg/ml, 0.05 ± 0.008µg/ml, 165.08 ± 31.5 min, 43.29 ± 12.5 min respectively). A significant elevation in anterior chamber C max and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5.68µg, but a significant difference was observed at a lower dose of quinidine (0.568µg). A decrease in vitreal elimination half-life and AUC was observed in the presence of verapamil relative to control. Ocular kinetics of fluorescein was studied to ascertain ocular barrier integrity in the presence of verapamil. Western-blot analysis of retina-choroid sections indicates expression of P-gp on rabbit retina-choroid. Conclusion. Results suggest the involvement of a multi drug efflux transporter on the retinal pigment epithelium and neural retina affecting the intraocular kinetics of its substrates following systemic and intravitreal administrations.