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Integrating Targeted Proteomics and Ocular Pharmacokinetics to Support PBPK Modeling of Carboxylesterase-Mediated Drug Metabolism in the Eye: A Case Study with Latanoprost Ophthalmic Solution
Li, Mengyue Niyangoda, Sayuri RAMISETTY, BHARGAVI SRIJA Johnson, Michael
Li, Mengyue
Niyangoda, Sayuri
RAMISETTY, BHARGAVI SRIJA
Johnson, Michael
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Abstract
Physiologically based pharmacokinetic (PBPK) modeling is increasingly used to support drug development and regulatory assessment. Yet, current ocular PBPK models primarily account for physicochemical and formulation properties of the drug and physiological characteristics of the eye, with limited consideration of local metabolic processes. Ocular tissues are enriched with hydrolases—particularly carboxylesterases (CESs)—that play critical roles in ocular local metabolism and activating ester prodrugs such as latanoprost.
This study aims to quantify CES protein expression across rabbit ocular sub-tissues and obtain ocular PK profiles of latanoprost following topical administration in rabbits. The resulting dataset will serve as a foundation for developing advanced ocular PBPK models incorporating CES- mediated metabolism, thereby enhancing the translational prediction of ocular drug disposition. Our study shows that signature peptide selection critically impacts CES quantification. RbCES1_pep2 yielded considerably higher and more reliable CES1 protein abundance than RbCES1_pep1, while RbCES2_pep1 produced higher CES2 levels than RbCES2_pep2. In rabbit ocular tissues, CES1 was most abundant in ICB, followed by cornea, RC, VH, and lens, and significantly lower in AH and tear film, aligns with human eye proteomics data.9 CES2 levels were generally lower than CES1, except in AH, highlighting tissue- specific CES isoforms expression across the rabbit ocular tissues. Correlation analysis suggested that CES1 is the primary enzyme responsible for latanoprost metabolism in rabbit liver, consistent with its small alcohol moiety. The in vivo ocular PK study revealed rapid corneal bioactivation of latanoprost to latanoprost acid, with the parent drug undetectable in AH. The high tear concentration of latanoprost acid despite low CES1 expression suggests additional enzymatic contribution or back-diffusion of the metabolite from the cornea.
Latanoprost acid showed a similar terminal half-life in both tear film and AH, suggesting a shared rate-limiting elimination process under our experimental conditions. This is likely due to reduced tear turnover and drainage in anesthetized rabbits, causing the entire anterior chamber to decline with the same apparent rate constant. Future study will focus on obtaining key kinetic parameters (such as the conversion rate in tear and cornea) to refine and validate the PBPK model integrating ocular metabolism and pharmacokinetics.
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<This is the poster from a presentation given at the American Association of Pharmaceutical Scientists 2025 PHarmsci 360 held in San Antonio, TX on 9/11/2025.
Date
2025-09-11
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University of Kansas
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LiM_2025.pdf
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Keywords
Ocular CES metabolism, Proteomics, Pharmacokinetics, Ocular PBPK