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An in vitro Investigation of Ocular Bioactivation Potential and the Role of CytochromeP450 2D Enzymes in Rat

Dumouchel, Jennifer, Argikar, Upendra, Spear, Jaimie, Brown, Ann, Dunne, Christine, Kramlinger, Valerie, Cirello, Amanda and Gunduz, Mithat (2017) An in vitro Investigation of Ocular Bioactivation Potential and the Role of CytochromeP450 2D Enzymes in Rat. Drug metabolism letters.. ISSN 1874-0758


Timolol is clinically administered topically (ocular) to reduce intraocular pressure and treat open-angle glaucoma. Ocular administration of timolol in low doses (0.5% w/v in the form of eye drops) has led to challenges for in vivo metabolite identification. An understanding of drug metabolism in the eye is important for clinical ocular therapeutics and potential drug candidates. We aimed to investigate the metabolism of timolol in rat ocular and liver S9 fractions, as well as rat ocular tissue and plasma following a 0.5% topical (ocular) dose of timolol. We explored the potential metabolic bioactivation in the eye/liver by conducting trapping studies for putative aldehyde and iminium intermediates that may arise from the morpholine functionality. This research is the first comprehensive report of ocular metabolism of timolol in rat. Oxidative metabolism of timolol to its major metabolite (M4) in ocular S9 compared with recombinant rat cytochrome P450 (CYP) isoforms support the possible role of rat ocular cytochromes P450 2D2, 2D4, and/or 2D18. Observation and primary report of N-acetyl-timolol (M5) is suggestive that the ocular N-acetyltransferases may also play a larger role in ocular disposition of timolol, a previously unreported finding. This study also indicates that in vitro hepatic metabolism is over-predictive of topically ocular dosed timolol. The research, herein, highlights the eye as an organ capable of first pass metabolism for topical drugs. Thus, new ophthalmologic considerations for studying and designing long term topical administration in preclinical species are needed in drug discovery.

Item Type: Article
Date Deposited: 15 Nov 2017 00:45
Last Modified: 15 Nov 2017 00:45


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