Comparative Transcriptomic Profiling of Drug Metabolizing Enzymes and Drug Transporters in Rabbit Ocular Sub-tissues, Liver, and Duodenum

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 the complex ocular tissues. 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 sub-tissues, including cornea, iris-ciliary body, vitreous humor, and retina-choroid complex. Rabbit liver and duodenum samples were also included to explore gene expression differences between eye, liver, and duodenum. The mRNA transcriptome of the six tissue types from six rabbits (three males and three females) was sequenced in a single run by RNA-seq for cross-tissue gene expression comparisons. A total of 387 DME and 127 DT genes were identified across the six tissues, and distinct expression patterns of DME and DT genes were observed between ocular sub-tissues vs. liver and duodenum and among different ocular sub-tissues. Furthermore, specific DMEs and DTs that were enriched in each tissue type were identified and relative gene expression of DMEs and DTs across the six tissue types were measured. These results will aid ophthalmic drug development by providing bases for ocular tissue-specific drug disposition/response and informing model-based prediction and interspecies extrapolation.