Ocular drug-metabolizing enzymes: focus on esterases

Area of Science:

• Ophthalmology
• Pharmacology
• Biochemistry

Background:

• The eye has a distinct metabolic profile, with limited cytochrome P450s (CYPs) and transferases, but abundant hydrolytic enzymes.
• Ocular drug metabolism is critical for prodrug activation and elimination, influencing therapeutic efficacy.
• Significant interspecies variations in ocular enzyme expression and activity are reported, impacting drug development.

Purpose of the Study:

• To review current knowledge on ocular phase I and II drug-metabolizing enzymes in humans and animal models.
• To focus on ocular esterases and their role in prodrug substrates within ophthalmic research.
• To identify knowledge gaps in ocular drug metabolism and species differences for translational studies.

Main Methods:

• Comprehensive literature survey of ocular drug-metabolizing enzymes.
• Analysis of enzyme expression and activity across different ocular tissues and species.
• Focus on cytochrome P450s (CYPs), transferases (including glutathione S-transferases - GSTs), and esterases.

Main Results:

• The eye exhibits restricted expression of major CYPs and most transferases, unlike the liver.
• Hydrolytic enzymes, particularly esterases, are abundant in various ocular tissues.
• Substantial interspecies variations in enzyme expression levels and activities were observed.

Conclusions:

• Detailed characterization of ocular enzymes and their species-specific differences is essential for ophthalmic drug development.
• Addressing knowledge gaps will improve the translation of preclinical findings to clinical applications in eye drug research.
• Understanding ocular esterases and their prodrug substrates is key for optimizing ophthalmic therapies.