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

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Abstract
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. 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 (5 mg/kg bodyweight) and intravitreally (5.68 microg and 0.568 microg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 +/- 6.47 min. microg/ml), maximum concentration achieved (Cmax) (0.095 +/- 0.011 microg/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. microg/ml, 0.05 +/- 0.008 microg/ml, 165.08 +/- 31.5 min, 43.29 +/- 12.5 min respectively). A significant elevation in anterior chamber Cmax and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5.68 micro g, but a significant difference was observed at a lower dose of quinidine (0.568 microg). 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. 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.