Acyl glucuronide reaction

Reaction is terminated by acetonitrile quenching, or by liquid-liquid extraction with water-immiscible organic solvent, provided that the extraction efficiency and the effect of the organic solvent on product stability are tested at the small scale. Based on properties of product, the pH of the reaction mixture should be adjusted before termination to allow maximal recovery of the product. For example, acid is usually added to the acyl-glucuronide product mixture at the end of the reaction to minimize acyl migration. 

FIGURE 8.9 Acyl glucuronides can act as electrophiles both through a direct SN2 reaction and after rearrangement of the acyl glucuronide. 

Boelsterli UA. Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions. Curr Drug Metab 2002 3(4) 439-450. 

Fig. 11.1. Regio-isomerization of acyl glucuronides. Migration of the /3-1-acyl group from C(l) to C(2) by intramolecular nucleophilic attack. Migration can continue to C(3) and then C(4). Such reactions are usually competitive with chemical hydrolysis [25][26],... 

U. Sidelmann, S.H. Hansen, C. Gavaghan, A.W. Nicholls, H.A.J. Carless, J.C. Lindon, I.D. Wilson, J.K. Nicholson, Development of a simple liquid chromatographic method for the separation of mixtures of positional isomers and anom-ers of synthetic 2-, 3- and 4-fluorobenzoic acid glucuronides formed via acyl migration reactions, J. Chromatogr. B Biomed. Sci. Appl. 685 (1996) 113-122. 

An important pathway of 0-glucuronidation is the formation of acyl-glucuronides. Substrates are anti-inflammatory arylacetic acids and aliphatic acids such as valproic acid (13). These metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins." Thus, acyl glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxihcation. 

A special class of acyl glucuronides are the carbamoyl glucuronides (reaction 4 in Fig. 

Fig. 31.29 Different metabolic pathways of p-amino-salicylic acid. Several conjugating enzymes are involved glycine TV-acyltransferases (reaction 1), UDP-glucuro-nosyltransferases (acyl-, ether-, A/-glucuronides, reactions 2, 4 and 6, respectively), sulfotransferases (reactions 3 and 5), A/-acetyltransferases (reaction 7).

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

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