An<i>in vitro</i>approach to investigate ocular metabolism of a topical, selective<b>β</b>1-adrenergic blocking agent, betaxolol

Bushee, Jennifer L.; Dunne, Christine E.; Argikar, Upendra A.

doi:10.3109/00498254.2014.987191

Cited by 10 publications

(14 citation statements)

References 27 publications

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“…To date, a few examples have been published from an early drugdiscovery mind set. The S9 fractions were used to characterize the ocular disposition of betaxolol, a commonly used topical therapy (Bushee et al, 2015). These S9 fractions have also been used to evaluate in vitro ocular metabolites of ketoconazole at clinically relevant concentrations (Cirello et al, 2017).…”

Section: Models Of Ocular Drug Disposition and Toxicitymentioning

confidence: 99%

“…It is important to note that metabolism in this section of the review refers to turnover in human liver-based cellular or subcellular fractions. Differences in ocular metabolism between laboratory animals and human species and differences in metabolic rates and profile between the eye and the liver are widely noted (Bushee et al, 2015;Argikar et al, 2016;Cirello et al, 2017) and may preclude direct preclinical translation of this data set. Lastly, considering the limited size of the data set used (n = 22), this initial approach requires further follow-up and refinement.…”

Section: Ocular Classification Systemmentioning

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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Section: Models Of Ocular Drug Disposition and Toxicitymentioning

confidence: 99%

Section: Ocular Classification Systemmentioning

confidence: 99%

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

et al. 2018

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“…There is sparse evidence for drug-metabolizing enzymes in ocular tissues of some animals-for example, ketoreductase activity in rabbits (Lee et al, 1988), monoamine oxidase in cows (Sparks et al, 1981), and cytochrome P450 mRNA in rats (Nakamura et al, 2005) and humans (Zhang et al, 2008). Recently, we reported a novel in vitro approach to investigate ocular metabolism (Bushee et al, 2015) in an effort to develop a simple, robust, and reproducible model to study ocular disposition of xenobiotics across preclinical species and humans.…”

Section: Introductionmentioning

confidence: 99%

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Argikar

Dumouchel

Dunne

et al. 2016

Drug Metabolism and Disposition

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Although ocular transport and delivery have been well studied, metabolism in the eye is not well documented, even for clinically available medications such as levobunolol, a potent and nonselective b-adrenergic receptor antagonist. Recently, we reported an in vitro methodology that could be used to evaluate ocular metabolism across preclinical species and humans. The current investigation provides detailed in vitro ocular and liver metabolism of levobunolol in rat, rabbit, and human S9 fractions, including the formation of equipotent active metabolite, dihydrolevobunolol, with the help of high-resolution mass spectrometry. 11 of the 16 metabolites of levobunolol identified herein, including a direct acetyl conjugate of levobunolol observed in all ocular and liver fractions, have not been reported in the literature. The study documents the identification of six human ocular metabolites that have never been reported. The current investigation presents evidence for ocular and hepatic metabolism of levobunolol via non-cytochrome P450 pathways, which have not been comprehensively investigated to date. Our results indicated that rat liver S9 and human ocular S9 fractions formed the most metabolites. Furthermore, liver was a poor in vitro surrogate for eye, and rat and rabbit were poor surrogates for human in terms of the rate and extent of levobunolol metabolism.

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“…In order to collect preliminary data on the course of the metabolism process and the structures of metabolites formed by the selected for comparison pharmaceutical substances, a detailed review of the available literature was performed [36,46,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63].…”

Section: Preliminary Characterization Of Metabolism Pathwaysmentioning

confidence: 99%

Photocatalysis as a Tool for in Vitro Drug Metabolism Simulation: Multivariate Comparison of Twelve Metal Oxides on a Set of Twenty Model Drugs

2019

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The constant development in the area of medicinal substances on the market and their subsequent progress in the field of drug analysis has become one of the reasons for the search for alternative, cheaper, and faster methods to determine the metabolism pathways of new molecular entities (NMEs). The simulation of transformation processes using photocatalysis is considered to be one of the promising methods. Although its effectiveness has been proven, the research has so far focused especially on titanium dioxide, while a more accurate comparison of the suitability of different photocatalysts in terms of their use in drug metabolism studies has not been performed. For this purpose, a set of twelve metal oxides was prepared and their photocatalytic efficiency in the direction of drug metabolism mimicking was checked on a model mixture of twenty medicinal substances differing both in chemical structure and pharmacological properties. Incubation with human liver microsomes (HLMs) was used as the reference method. The metabolic profiles obtained with the use of LC-MS analysis were compared using multidimensional chemometric techniques; and the graphic presentation of the results in the form of PCA plot and cluster dendrogram enabled their detailed interpretation and discussion. All tested photocatalysts confirmed their effectiveness. However, the exact outcome of the study indicate advantage of the WO3-assisted photocatalysis over other metal oxides.

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Anin vitroapproach to investigate ocular metabolism of a topical, selectiveβ1-adrenergic blocking agent, betaxolol

Cited by 10 publications

References 27 publications

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

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

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Photocatalysis as a Tool for in Vitro Drug Metabolism Simulation: Multivariate Comparison of Twelve Metal Oxides on a Set of Twenty Model Drugs

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