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Keywords: UGT, acyl glucuronides, glucuronidation, reactivity, stability, bioactivation, thioacyl glutathione, methoxylamine 1. Introduction Glucuronidation is the conjugation of glucuronic acid to various functional groups, catalyzed by UDP-glucuronosyl-transferases UGTs in the presence of activated co-substrate, uridine diphosphoglucuronic acid UDPGA [ 1 , 2 ]. N-carbamoyl glucuronides, glucuronides formed at carbon and selenium atoms, discrete and linked di-glucuronides are examples of uncommon glucuronides [ 5 ].
Acyl glucuronides are formed when carboxylic acid moieties are present or eventually unmasked i. Bilirubin mono- and di-glucuronides are examples of acyl glucuronides of endogenous molecules [ 6 ]. Non-steroidal anti-inflammatory drugs with acyl groups are a class of compounds that are metabolized via biotransformation to acyl glucuronides [ 7 ].
Specifically, acyl glucuronides of non-steroidal anti-inflammatory drugs undergo active uptake in the gut, followed by intracellular enzymatic and non-enzymatic hydrolysis to release the respective parent drugs. Johansson, Paul D. Kemmitt, Bo T. Noeske, Andreas Nordin, Charles J.
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Historically, researchers have proposed numerous conditions and methodologies to evaluate the reactivity and preclinical toxicity of carboxylic acid containing drugs, because of their corresponding acyl glucuronides. Balzer, Shuojin Wang, and Weiping Tang. The Journal of Physical Chemistry B , 19 ,
Kevin Park, and, Ian D. Kemmitt, Graham J. David A. Bauer, Alan M.
Analytical Chemistry , 79 22 , Cited By This article is cited by 75 publications. Akiko Baba and Tadao Yoshioka. The reactivity and lack of stability of an acyl glucuronide for a clinical candidate could pose ma-jor developability concerns.
Balzer, Shuojin Wang, and Weiping Tang. New series of N-aryl- and N-heteroaryl-d-glucuronamides as potential anticancer agents: synthesis and spectroscopic analysis. Carbohydrate Research , , Mayers, Martin J. Heskes, Jason Q. Maggs, B.