Identification of a new allele of Es-1 segregating in an inbred strain of mice

Soares, E.R.

doi:10.1007/bf00502119

Cited by 13 publications

(8 citation statements)

References 4 publications

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“…Mouse, rat, and rabbit, however, have a high abundance of plasma Ces and the HXEL sequence is absent in these species, resulting in secretion of Ces into the blood [47]. Mouse strains that lack plasma esterase activity are available, i.e ., Es1e and Es1e/scid [48, 49]. Plasma esterase-deficient mice are useful to evaluate the impact of plasma esterases on PK.…”

Section: Tissue Distribution and Species Differencementioning

confidence: 99%

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

2019

CDM

145

102

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Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, and bioconverting prodrugs and soft drugs. Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Marked species differences in tissue distribution and catalytic activity have been observed for CES enzymes. Careful evaluation is required when selecting animal models for human translation. Monkeys appear to be more predictive of human pharmacokinetics than other species for CES substrates. In vitro - in vivo extrapolation of clearance is still in its infancy for CES enzymes and further exploration is needed. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

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Section: Tissue Distribution and Species Differencementioning

confidence: 99%

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

2019

CDM

145

102

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“…The Es1 e mice were originally generated in the 1970’s using mutagen treated sperm and were subsequently found to lack a circulating esterase (62). Two decades later, these mice were retrieved from Jackson labs and plasma obtained from these animals was essentially unable to hydrolyze CPT-11 (59).…”

Section: Carboxylesterasementioning

confidence: 99%

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

Argikar

Potter

Hutzler

et al. 2016

AAPS J

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Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High throughput metabolic stability screening has enabled advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non CYP-mediated metabolism. UGTs, esterases and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro–in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of liver, extra-hepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extra-hepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and inter-subject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non CYP-mediated metabolism; understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation; predicting human clearance and avoid costly clinical failures when non-CYP mediated metabolic pathways are predominant.

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“…Incubation of radiolabeled disaccharide with mouse serum for 3 hours resulted in extensive removal of the acetyl groups due to serum esterases but no hydrolysis of the glycosidic linkages. Because uptake of the compound depends on the presence of the acetyl groups to facilitate passive diffusion (16), we examined the stability of the compound in serum obtained from an esterasereduced Es1(e) mouse, which has a hypomorphic allele of serum Es-1 (21). Acetylated disaccharide in serum from Es1(e) mice was stable for several hours, which approximated conditions in human serum (22).…”

Section: Resultsmentioning

confidence: 99%

A Disaccharide-Based Inhibitor of Glycosylation Attenuates Metastatic Tumor Cell Dissemination

Brown¹,

Fuster

Li³

et al. 2006

Clinical Cancer Research

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Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLe X ) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis.The glycosylation inhibitor, per-O-acetylated GlcNAch1,3Galh-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLe X in tumor cells.To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells. Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectindeficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model. Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLe X -and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLe X in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or sLe X -dependent inflammation. Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycosidebased therapy for the treatment of hematogenous dissemination of tumor cells.

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Identification of a new allele of Es-1 segregating in an inbred strain of mice

Cited by 13 publications

References 4 publications

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

A Disaccharide-Based Inhibitor of Glycosylation Attenuates Metastatic Tumor Cell Dissemination

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