Abstract
Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.
Highlights
Glaucoma is a progressive neurodegenerative disorder of the eye and the leading cause of irreversible blindness worldwide
Using an liquid chromatography-mass spectrophotometry/mass spectrophotometry (LC-MS/MS)-based assay to detect cromakalim prodrug 1 (CKLP1) and levcromakalim simultaneously, we report the pharmacokinetic parameters of CKLP1 following intravenous and topical eye administration of the drug in Dutch-belted pigmented rabbits
Collection of tissues and fluids for pharmacokinetic and pharmacodynamic studies For rabbits injected with CKLP1 intravenously, central ear vein blood was collected at 5 min, 15 min, 30 min, 60 min, 2h, 4h, 8h and 24h following dosing
Summary
Glaucoma is a progressive neurodegenerative disorder of the eye and the leading cause of irreversible blindness worldwide. Several commercially available KATP channel openers were shown to lower IOP in ex vivo and in vivo experimental model systems [9,10,11]. Since none of these openers are water-soluble and not suitable for human application, we developed an aqueous soluble prodrug based on the structure of levcromakalim [12]. Topical treatment of CKLP1 to the eye results in similar IOP reduction as found with levcromakalim [12, 13]. The safety profile and systemic distribution of CKLP1 were evaluated in Dutch-belted pigmented rabbits following once daily instillation of eye drops for 90 days
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