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G. Mishra, S. Hariharan, R. Krishna, D. Pal, A. Mitra; Screening of Anti-Glaucoma Drugs in vitro for Interactions With P-Glycoprotein. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2556.
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The objective of this study was to screen the in vitro interaction of intraocular pressure lowering ophthalmic formulations with P-glycoprotein (P-gp)
Madin-Darby Canine Kidney (MDCK) cells transfected with MDR-1 gene and cultured rabbit primary corneal epithelial cells (rPCECs) were employed as models for in vitro studies. Bimatoprost (Lumigan®), dorzolamide HCl (Trusopt®), dorzolamide HCl and timolol maleate (Cosopt®), brimonidine tartrate (Alphagan®), brinzolamide (Azopt®) and timolol hemihydrate (Betimol®) were the intraocular pressure lowering ophthalmic formulations that were selected for this study. [14C] Erythromycin was chosen as a substrate for P-gp to study the interaction. The medications were used at an inhibitory concentration of 500 µM.
Uptake of [14C] Erythromycin increased by more than 3 fold in the presence of Lumigan® (bimatoprost) in MDCK-MDR1 and rPCECs. These results suggest that bimatoprost, an active ingredient in Lumigan®, might be interacting with P-gp. All the other intraocular pressure lowering ophthalmic formulations did not alter the uptake of [14C] Erythromycin indicating that the active ingredient in those formulations may not be substrates for the efflux proteins. Further, uptake studies using bimatoprost as the substrate, alone and in the presence of GF 120918A (specific P-gp inhibitor), showed significantly higher cellular accumulation of bimatoprost in the presence of the inhibitor. Bi-directional flux experiments using MDCK-MDR1 cells also supported the finding that bimatoprost interacted with P-gp. The efflux ratio (Papp(BL- AP)/Papp(AP-BL)) of bimatoprost was found to be 3.14 and Papp(AP-BL) increased 2 fold in the presence of GF 120918A. Interestingly, other prostaglandin analogs such as latanoprost and travoprost did not appear to interact with P-gp.
Bimatoprost, the active ingredient in Lumigan®, was found to inhibit the uptake of [14C] Erythromycin, which indicates that bimatoprost may be a substrate for P-gp. This finding was further confirmed when cellular accumulation of bimatoprost increased significantly in the presence of GF 120918A. Since human corneal epithelium has been functionally characterized for the presence of P-gp, efflux of bimatoprost out of the corneal epithelium could play a role in restricting its ocular bioavailability.Financial Support: Supported by NIH grants R01 EY 09171-12 & R01 EY 10659-10 and Allergan Inc.
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