Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

Argikar, Upendra A.; Dumouchel, Jennifer L.; Kramlinger, Valerie M.; Cirello, Amanda; Gunduz, Mithat; Dunne, Christine E.; Sohal, Bindi

doi:10.1016/j.xphs.2017.03.008

Cited by 20 publications

(12 citation statements)

References 55 publications

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“…During ophthalmic administrations in rabbits, it has been shown that atropine has good ocular bioavailability via both transcorneal and transconjunctival-scleral routes [ 59 ]. Unfortunately and to the best of our knowledge, atropine metabolism in the eye has not been studied despite there being a clear incentive to do so, like for other drugs [ 60 ]. There is therefore very little information available about the possibility of the natural formation of tropic acid in the eye after atropine topical application or, as stated previously, about tropic acid’s ophthalmic toxicity.…”

Section: Discussionmentioning

confidence: 99%

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

et al. 2020

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Myopia is an ophthalmic condition affecting more than 1/5th of the world population, especially children. Low-dose atropine eyedrops have been shown to limit myopia evolution during treatment. However, there are currently no commercial industrial forms available and there is little data published concerning the stability of medications prepared by compounding pharmacies. The objective of this study was to evaluate the stability of two 0.1 mg/mL atropine formulations (with and without antimicrobiobial preservatives) for 6 months in two different low-density polyethylene (LDPE) multidose eyedroppers. Analyses used were the following: visual inspection, turbidity, chromaticity measurements, osmolality and pH measurements, atropine quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, atropine quantification was also performed on the drops emitted from the multidose eyedroppers. All tested parameters remained stable during the 6 months period, with atropine concentrations above 94.7% of initial concentration. A breakdown product (tropic acid) did increase slowly over time but remained well below usually admitted concentrations. Atropine concentrations remained stable during the in-use study. Both formulations of 0.1 mg/mL of atropine (with and without antimicrobial preservative) were proved to be physicochemically stable for 6 months at 25 °C when stored in LDPE bottles, with an identical microbial shelf-life.

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Section: Discussionmentioning

confidence: 99%

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

et al. 2020

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“…Analytical challenges and sample availability have led to questions regarding how, why, and when it is appropriate to study ocular metabolism in vivo and in vitro (Argikar et al, 2017b). The review notes a resurgence in xenobiotic ocular metabolism, yet a comprehensive in vitro model to study the eye for metabolism and subsequent transport is not available as compared to the way one would traditionally characterize hepatic metabolism.…”

Section: In Vitro Models Of Ocular Metabolismmentioning

confidence: 99%

“…The model can also be used in lead optimization to drive structure-metabolism relationships by asking the right question at the right time. Examples at both ends of the drug discovery process may expand the way industry studies new ophthalmic treatments (Argikar et al, 2017b;Khojasteh et al, 2017).…”

Section: Models Of Ocular Drug Disposition and Toxicitymentioning

confidence: 99%

“…The role of melanin in ocular drug distribution is possibly one of the most controversial topics in ocular pharmacology and drug disposition. A detailed deliberation of melanin binding of drugs and the subsequent impact has been written elsewhere (Argikar et al, 2017b). Therefore, extrapolation of ocular drug exposure, disposition, and potency/efficacy data from in vitro models with or without melanin to in vivo animal models must be conducted with caution.…”

Section: Downloaded Frommentioning

confidence: 99%

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Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

et al. 2018

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The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

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“…[1,2] Nutrients and drugs are actively or passively transported through the corneal epithelial barrier, followed by their intracellular metabolism, modification, and secretion of the corresponding metabolites. Although many metabolic pathways (e.g., oxidative, hydrolytic, reductive, and conjugative pathways) [3,4] and transporters [5,6] in the cornea have been investigated, the spatiotemporal mechanisms of the in situ metabolism and transportation of drugs through the human corneal barrier are barely known, owing to the technical difficulties in the current corneal experimental platforms as well as the lack of analytical tools that non-invasively enable longitudinal metabolome monitoring in small volumes. [7,8] Moreover, while the current in vitro corneal models that use cell-culture inserts (e.g., a transwell system) have been investigated, they only provide a two-dimensional structure of the corneal epithelial cells, which is physiologically different that in the cornea.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Determination of Metabolite Activities in Multiple Corneal Epithelium Barriers on a Chip

Abdalkader

Chaleckis

Wheelock

et al. 2021

Preprint

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The corneal epithelial barrier maintains the metabolic activities of the ocular surface by regulating membrane transporters and metabolic enzymes responsible for the homeostasis of the eye as well as the pharmacokinetic behavior of drugs. Despite its importance, no established biomimetic in vitro methods are available to perform the spatiotemporal investigation of corneal metabolism and determine the transportation of endogenous and exogenous molecules. This study introduces multiple corneal epithelium barriers on a chip, namely, Cornea-Chip, which enables the spatiotemporal collection as well as analysis of micro-scaled extracellular metabolites from both the apical and basolateral sides of the barriers. Longitudinal samples collected during 48 h period were analyzed using untargeted liquid chromatography–mass spectrometry metabolomics method, and 104 metabolites were annotated. The shifts in extracellular metabolites and quantitative analysis of the mRNA associated with membrane transporters could allow the investigation of the correlation between the expression of and the secretion and transportation of metabolites across the polarized corneal epithelial barrier. The Cornea-Chip might provide a non-invasive, simple, and effectively informative method to determine pharmacokinetics and pharmacodynamics as well as to discover novel biomarkers for drug toxicological and safety tests as an alternative to animal experiments.

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Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

Cited by 20 publications

References 55 publications

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

Spatiotemporal Determination of Metabolite Activities in Multiple Corneal Epithelium Barriers on a Chip

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