Comparative transcriptomic profiling of drug-metabolizing enzymes and drug transporters in rabbit ocular subtissues,...

The increasing prevalence of diabetes and the aging population have led to a growing market 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 complex ocular tissues. The rabbit is the most commonly used preclinical model for human ocular diseases. The purpose of this study was to compare relative gene expression of DMEs and DTs in various rabbit ocular subtissues, including cornea, iris-ciliary body, vitreous humor, and retina-choroid complex. Rabbit liver and duodenum samples were also included to investigate gene expression differences among the eye, liver, and duodenum. The mRNA transcriptome of the 6 tissue types from 6 rabbits (3 males and 3 females) was sequenced in a single run using RNA-seq for cross-tissue gene expression comparisons. A total of 387 DME and 128 DT genes were identified across the 6 tissues, and distinct expression patterns of DME and DT genes were observed between ocular subtissues vs. liver and duodenum and among different ocular subtissues. Furthermore, specific DMEs and DTs that enriched in each tissue type were identified and relative gene expression of DMEs and DTs across the 6 tissue types was measured. These results are expected to aid ophthalmic drug development by providing a basis for ocular tissue-specific drug disposition/response and informing model-based predictions and interspecies extrapolation. SIGNIFICANCE STATEMENT: This study represents the first comprehensive comparative transcriptomic analysis of drug-metabolizing enzymes and drug transporters in rabbit ocular subtissues, with comparisons to key metabolic organs such as liver and duodenum. Our findings highlight critical tissue-specific differences that have significant implications for ophthalmic drug development and ocular drug delivery systems. The quantitative gene expression levels of drug-metabolizing enzymes and drug transporters in the rabbit eye will aid investigations into ocular drug metabolism and disposition in both preclinical and clinical settings.