Ocular non-P450 oxidative, reductive, hydrolytic, and conjugative drug metabolizing enzymes

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

doi:10.1080/03602532.2017.1322609

Cited by 20 publications

(14 citation statements)

References 130 publications

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“…First pass metabolism is a process in which oral drug administration results in drug metabolism in the liver. When the drug passes directly from the intestine into the hepatic PV it is rapidly cleared in the liver via drug metabolizing enzymes, transporters and secretion through the bile (Andrews et al, 2017;Argikar et al, 2017;Mariappan et al, 2017;Miron et al, 2017). This rapid clearance of drugs decreases therapeutic efficacy of the orally administered drug.…”

Section: Bypass Of First Pass Metabolism In the Liver By Targeting Lymentioning

confidence: 99%

Emerging Roles for Lymphatics in Chronic Liver Disease

2020

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Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing novel therapeutics. Common characteristics of CLD include steatosis, inflammation, and cholesterol accumulation in the liver. While the lymphatic system in the liver has largely been overlooked, the liver lymphatics, as in other organs, are thought to play a critical role in maintaining normal hepatic function by assisting in the removal of protein, cholesterol, and immune infiltrate. Lymphatic growth, permeability, and/or hyperplasia in non-liver organs has been demonstrated to be caused by obesity or hypercholesterolemia in humans and animal models. While it is still unclear if changes in permeability occur in liver lymphatics, the lymphatics do expand in number and size in all disease etiologies tested. This is consistent with the lymphatic endothelial cells (LEC) upregulating proliferation specific genes, however, other transcriptional changes occur in liver LECs that are dependent on the inflammatory mediators that are specific to the disease etiology. Whether these changes induce lymphatic dysfunction or if they impact liver function has yet to be directly addressed. Here, we will review what is known about liver lymphatics in health and disease, what can be learned from recent work on the influence of obesity and hypercholesterolemia on the lymphatics in other organs, changes that occur in LECs in the liver during disease and outstanding questions in the field.

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Section: Bypass Of First Pass Metabolism In the Liver By Targeting Lymentioning

confidence: 99%

Emerging Roles for Lymphatics in Chronic Liver Disease

2020

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“…Although a complete ocular model for studying drug metabolism is not available, renewed emphasis on the eye could provide future model improvements. A question not answered by many models is the importance of the lens in xenobiotic metabolism in addition to its protective role, where glutathione S-transferase and N-acetyltransferase activities are important (Argikar et al, 2017a). Transitioning from healthy donors and nonpigmented animal models may or may not be an ideal model for studying ophthalmic disease state in humans.…”

Section: Models Of Ocular Drug Disposition and Toxicitymentioning

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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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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“…Finally, there is no knowledge on the ocular expression and activity of AADAC in the literature. 43 To understand the biotransformation capacity in the eye and the risk of the formation of toxic metabolites from extended drug exposure from ocular implants, the metabolic profiling of individual ocular tissues in all preclinical species and in humans is crucial. A more detailed characterization of the catalytic and expression properties of ocular esterases is also important in the design of ophthalmic (pro)drugs and drug conjugates and in understanding the hydrolysis of drugs entering the eye from the systemic circulation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…A review on global proteomics studies indicated that CES1 is detectable in most human ocular tissues except aqueous humor but quantitative expression data is nonexistent, and information on CES expression in other species is lacking, hampering translational studies. Finally, there is no knowledge on the ocular expression and activity of AADAC in the literature . To understand the biotransformation capacity in the eye and the risk of the formation of toxic metabolites from extended drug exposure from ocular implants, the metabolic profiling of individual ocular tissues in all preclinical species and in humans is crucial.…”

Section: Introductionmentioning

confidence: 99%

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

et al. 2021

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Hydrolytic reactions constitute an important pathway of drug metabolism and a significant route of prodrug activation. Many ophthalmic drugs and prodrugs contain ester groups that greatly enhance their permeation across several hydrophobic barriers in the eye before the drugs are either metabolized or released, respectively, via hydrolysis. Thus, the development of ophthalmic drug therapy requires the thorough profiling of substrate specificities, activities, and expression levels of ocular esterases. However, such information is scant in the literature, especially for preclinical species often used in ophthalmology such as rabbits and pigs. Therefore, our aim was to generate systematic information on the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC) in seven ocular tissue homogenates from these two species. The hydrolytic activities were measured using a generic esterase substrate (4-nitrophenyl acetate) and, in the absence of validated substrates for rabbit and pig enzymes, with selective substrates established for human CES1, CES2, and AADAC ( d -luciferin methyl ester, fluorescein diacetate, procaine, and phenacetin). Kinetics and inhibition studies were conducted using these substrates and, again due to a lack of validated rabbit and pig CES inhibitors, with known inhibitors for the human enzymes. Protein expression levels were measured using quantitative targeted proteomics. Rabbit ocular tissues showed significant variability in the expression of CES1 (higher in cornea, lower in conjunctiva) and CES2 (higher in conjunctiva, lower in cornea) and a poor correlation of CES expression with hydrolytic activities. In contrast, pig tissues appear to express only CES1, and CES3 and AADAC seem to be either low or absent, respectively, in both species. The current study revealed remarkable species and tissue differences in ocular hydrolytic enzymes that can be taken into account in the design of esterase-dependent prodrugs and drug conjugates, the evaluation of ocular effects of systemic drugs, and in translational and toxicity studies.

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Ocular non-P450 oxidative, reductive, hydrolytic, and conjugative drug metabolizing enzymes

Cited by 20 publications

References 130 publications

Emerging Roles for Lymphatics in Chronic Liver Disease

Emerging Roles for Lymphatics in Chronic Liver Disease

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

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

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