NSAID Acyl Glucuronides and Enteropathy.

14:59 EDT 2nd September 2014 | BioPortfolio

Summary of "NSAID Acyl Glucuronides and Enteropathy."

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acid-containing compounds that are conjugated in the liver to acyl glucuronides and excreted across the hepatocanalicular membrane into bile. Chronic and acute NSAID use has not only been associated with gastric injury but also increasingly recognized to cause small intestinal injury (enteropathy). The mechanisms of NSAID enteropathy are still unknown, but a combination of topical effects (including mitochondrial injury) combined with inhibition of COX1/2, followed by an inflammatory response triggered by LPS-mediated activation of LTR4 on macrophages, have been implicated in the pathogenesis. Some of the nucleophilic proteins that are targeted by the electrophilic NSAID acyl glucuronides or their iso-glucuronides have been identified both in bile canaliculi and on the apical membrane domain of enterocytes (e.g., aminopeptidase N); however, the mechanistic role of covalent adducts has remained enigmatic. In contrast, it has become increasingly clear that acyl glucuronide formation is a major toxicokinetic determinant, in that the drug conjugates are a transport form delivering the drug to the more distal parts of the jejunum/ileum, where the glucuronic acid moiety is cleaved off the aglycone due to higher local pH and the presence of bacterial β-glucuronidase. Through this mechanism, high local concentrations of the parent NSAID can be attained, potentially leading to local tissue injury. Thus, even if one considers the formation of acyl glucuronides not as a potentially dangerous toxophore by virtue of their protein-reactivity, acyl glucuronides could still be a red flag in drug development if excreted at high rates into bile and delivered to more distal areas of the small intestine where high amounts of parent drug is released.

Affiliation

Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, 69 North Eagleville Road Unit 3092, Storrs, CT 06269-3092, USA. urs.boelsterli@uconn.edu.

Journal Details

This article was published in the following journal.

Name: Current drug metabolism
ISSN: 1875-5453
Pages:

Links

PubMed Articles [387 Associated PubMed Articles listed on BioPortfolio]

NSAID-gastroenteropathy: new aspects of pathogenesis and prevention.

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most commonly used medications because of their effectiveness in reducing pain and inflammation. Inhibitors of gastric acid secretion can...

NSAID-Induced Enteropathy in Rheumatoid Arthritis Patients with Chronic Occult Gastrointestinal Bleeding: A Prospective Capsule Endoscopy Study.

Background. The purpose of study was to evaluate the diagnostic yield of capsule endoscopy for NSAID-induced enteropathy and clinical, laboratory, and endoscopic characteristics of disease in patients...

Meckel's diverticulum detected by virtual enteroscopy in a patient with nonsteroidal anti-inflammatory drug-induced enteropathy.

A 68-year-old female presented to our hospital with abdominal discomfort and obscure gastrointestinal bleeding. She had been prescribed aspirin for retinal venous occlusion. Video capsule endoscopy (V...

Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-γ

In previous reports, hesperidin, a flavonoid glucoside from citrus fruit, is hydrolyzed to hesperetin, an aglycone of hesperidin, and converted to the hesperetin glucuronides (H7-OG and H3'-OG) in viv...

Etoricoxib: a safe alternative for NSAID intolerance in Asian patients.

NSAID intolerance is not uncommon. Etoricoxib, a cox-2 inhibitor NSAID, has been shown to be a safe alternative in these patients. This study aims to determine the rate of NSAID intolerant patients wh...

Clinical Trials [79 Associated Clinical Trials listed on BioPortfolio]

Adherence to Gastro-Protection in Non-Steroidal Anti-Inflammatory Drug (NSAID) Using Patients

Prospective multicentric study to evaluate the compliance of gastroprotective treatment in NSAID patients at risk of GI complications. Secondary objectives: To identify the factors associa...

Plasma Citrulline Concentration in Tropical Enteropathy

Citrulline is an amino acid produced in the intestine and in the liver, but the liver does not contribute significantly to circulating citrulline concentrations. The intestine is thus the ...

Safety and Efficacy of ODSH in Protein Losing Enteropathy Secondary to Single Ventricle Palliative Surgery

Protein Losing Enteropathy (PLE) is a serious and sometimes fatal medical condition that may develop in subjects with congenital cardiac disease for which a palliative procedure known as t...

Characterization Phenotypic and Genetic Study of the Intestinal Epithelial Dysplasia or Tufting Enteropathy (TE)

This PHRC is centred on the intestinal epithelial dysplasia ( DEI) or " tufting enteropathy " or TE the clinical and histo-pathological descriptions of which are specified well to the dige...

Treatment of Mild Enteropathy Celiac Disease

The main purpose of this study is to evaluate the natural history of gluten sensitivity in endomysial antibody positive adults with celiac disease suspicion, who were found to have a only ...

Medical and Biotech [MESH] Definitions

An NAD-dependent enzyme that catalyzes the oxidation of acyl-[acyl-carrier protein] to trans-2,3-dehydroacyl-[acyl-carrier protein]. It has a preference for acyl groups with a carbon chain length between 4 to 16.

An enzyme that catalyzes the oxidation of acyl-[acyl-carrier protein] to trans-2,3-dehydroacyl-[acyl-carrier protein] in the fatty acid biosynthesis pathway. It has a preference for acyl derivatives with carbon chain length from 4 to 16.

A syndrome characterized by chronic, well-established DIARRHEA (greater than one month in duration) without an identified infectious cause after thorough evaluation, in an HIV-positive individual. It is thought to be due to direct or indirect effects of HIV on the enteric mucosa. HIV enteropathy is a diagnosis of exclusion and can be made only after other forms of diarrheal illness have been ruled out. (Harrison's Principles of Internal Medicine, 13th ed, pp1607-8; Haubrich et al., Bockus Gastroenterology, 5th ed, p1155)

An enzyme of long-chain fatty acid synthesis, that adds a two-carbon unit from malonyl-(acyl carrier protein) to another molecule of fatty acyl-(acyl carrier protein), giving a beta-ketoacyl-(acyl carrier protein) with the release of carbon dioxide. EC 2.3.1.41.

Consists of a polypeptide chain and 4'-phosphopantetheine linked to a serine residue by a phosphodiester bond. Acyl groups are bound as thiol esters to the pantothenyl group. Acyl carrier protein is involved in every step of fatty acid synthesis by the cytoplasmic system.

Search BioPortfolio:
Advertisement

Relevant Topic

Pharmacy
Latest News Clinical Trials Research Drugs Reports Corporate
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Advertisement