Pharmacological and pharmacokinetic profile of the novel ocular hypotensive prodrug CKLP1 in Dutch-belted pigmented rabbits
| Autor: | Tommy A. Rinkoski, Cheryl R. Hann, Uttio Roy Chowdhury, Michael P. Fautsch, Peter I. Dosa, Bradley H. Holman, Joel M. Reid, Rachel A. Kudgus, Cindy K. Bahler |
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| Rok vydání: | 2020 |
| Předmět: |
Eye Diseases
Physiology Administration Topical Eye disease Glaucoma Pharmacology Eye Pharmacokinetic Analysis Mass Spectrometry Cornea chemistry.chemical_compound 0302 clinical medicine Elimination Half-Life Calculation Blood plasma Medicine and Health Sciences Prodrugs Mammals 0303 health sciences Multidisciplinary Pro-Drugs Eukaryota Drugs Animal Models Eye Muscles Prodrug Body Fluids Blood Experimental Organism Systems Vertebrates Leporids Medicine Administration Intravenous Female Potassium channel opener Rabbits Anatomy Research Article Cromakalim Ocular Anatomy Science Cmax Research and Analysis Methods Blood Plasma Aqueous Humor 03 medical and health sciences Pharmacokinetics Ocular System medicine Animals 030304 developmental biology business.industry Organisms Biology and Life Sciences medicine.disease Vitreous Body Ophthalmology Pharmacologic Analysis chemistry Amniotes Animal Studies 030221 ophthalmology & optometry Eyes sense organs business Head Chromatography Liquid |
| Zdroj: | PLoS ONE, Vol 15, Iss 4, p e0231841 (2020) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0231841 |
| Popis: | 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 ( |
| Databáze: | OpenAIRE |
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