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Comparative Transcriptomic Profiling of Drug-Metabolizing Enzymes and Drug Transporters in the Rabbit Ocular Sub-tissues
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Abstract
The increasing prevalence of diabetes and aging population has led to a growing market demand for ophthalmic pharmaceutical drugs. However, the development of ophthalmic drugs is hampered by the poor understanding of drug metabolizing enzymes (DMEs) and drug transporters (DTs) in the ocular sub-tissues. DMEs play important roles in the bioactivation of prodrugs and the detoxication of drugs, while DTs can facilitate or limit drug exposure to the site of action1. Rabbit is the most commonly used animal model to study ocular diseases and develop ophthalmic drugs. However, rabbit ocular DMEs and DTs have not been systematically characterized for their expression in ocular sub-tissues or compared to other major organs of drug disposition, e.g., liver and duodenum. This knowledge gap hinders precise extrapolation of ocular pharmacokinetic and pharmacodynamic data from rabbits to humans. As such, the goal of this study was to determine the localization and relative gene expression levels of DMEs and DTs in various rabbit ocular sub- tissues, including cornea, iris-ciliary body (ICB), vitreous humor (VH), and retina/choroid complex (RC), and to compare them to the rabbit liver and duodenum using RNA-seq.
Our study demonstrates the distinct expression patterns of DMEs and DTs in ocular sub-tissues compared to the liver and duodenum, highlighting the eye's unique capacity for drug metabolism and transport. While hepatic P450s show little to no expression in the eye, certain P450s involved in sterol and vitamin A metabolism are present. Hydrolytic enzymes, such as CES1, EPHX, and various peptidases, are abundantly expressed, along with several oxidative and reductive enzymes, indicating the eye has a high capacity for phase I drug metabolism. Among phase II DMEs: GSTs are highly abundant, while SULT1A1 and SULT4A1 are expressed at moderate levels. In contract, UGTs are expressed at low level in the eye. Efflux transporters, including most of the ABC family and MATE1, show high expression in ocular tissues, especially in the RC and ICB, reflecting the protective role in limiting the absorption of foreign molecules into the eye. Finally, several influx transporters, such as OATPs, OAT1, OCTN2, and BOCTs, also exhibit appreciable levels of expression in the eye, further highlighting the eye’s ability to regulate drug absorption and distribution. This comprehensive expression profile provides valuable insights into ocular drug disposition, which are expected to aid in the optimization of drug delivery strategies for ophthalmic therapies, improve interspecies extrapolation between rabbits and humans, and expedite the development of ophthalmic drugs.
Description
This poster was presented at American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 on 10/21/2024.
Date
2024-10-21
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University of Kansas
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Keywords
Ocular, Drug metabolism, Drug transporter, RNA-seq, Transcriptomics