Glucuronides, acyl

The active metabolite of this drug is mycophenolic acid (MPA), which inhibits IMPDH, too. MPA is metabolized in vivo by glucuronidation. It has to be noted that its acyl glucuronide inhibits EVDPDH with similar potency compared to the parent compound. 

These incubations are often carried out at 37 °C for 1-2 h. At different time points, 20-200 /aL of incubation mixture is withdrawn from each incubation and mixed with equal volume of ice-cold acetonitrile by vortexing. For preparation of acyl glucuronide, ice-cold acetonitrile containing 1% of formic acid is used to minimize acyl-migration [3,14]. After centrifugation at 13 000 rpm for 5-15 min, the supernatant (10-30 /aU) is analyzed by high-performance liquid chromatography (HPUC)-UV-MS. The metabolite of interest is identified based on HPLC retention time, UV spectrum and MS/MS data. Conversion yield is estimated based on UV absorption peak areas. A suitable in vitro enzyme system for scale-up is then... 

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. 

Mark, J., Bailey, M.J., Ronald, G. and Dickinson, R.G. (2003) Acyl glucuronide reactivity in perspective biological consequences. Chemico-Biological Interactions, 145, 117-137. 

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

Spahn-Langguth H, Benet LZ. Acyl glucuronides revisited is the glucuronidation process a toxification as well as a detoxification mechanism. Drug Metab Rev 1992 24 5-47. 

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. 

Sallustio, B.C., Purdie, Y.J., Birkett, D.J. and Meffin, P.J. (1989). Effect of renal dysfunction on the individual components of the acyl-glucuronide futile cycle. J. Pharmacol. Exp. Ther. 25 288-294. 

Acyl glucuronides (i.e., ester glucuronides of general structure 11.6) are formed as conjugates of carboxylic acids. These compounds are rather uniquely reactive a) they are far more sensitive to chemical hydrolysis than ether... 

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],... 

A quite comprehensive study was reported on the enzymatic hydrolysis of zenarestat acyl glucuronide [31]. The major metabolite of the aldose reductase inhibitor zenarestat (11.8) in humans and rats is the acyl glucuronide. This compound was unstable at physiological pH, being converted to its positional isomers and to the aglycone with a global tl/2 value of 25 min at pH 7.4 and 37°. In both rat and human blood, hydrolysis was accelerated by the... 

H. Spahn-Langguth, L. Z. Benet, Acyl Glucuronides Revisited Is the Glucuronidation Process a Toxification as well as a Detoxification Mechanism , Drug Metab. Rev. 1992, 24, 5 - 48. 

F. M. Brunelle, P. K. Verbeeck, Conjugation-Deconjugation Cycling of Diflunisal via Beta-Glucuronidase Catalyzed Hydrolysis of Its Acyl Glucuronide in the Rat , Life Sci. 

M. Wang, R. G. Dickinson, Disposition and Covalent Binding of Diflunisal and Diflunisal Acyl Glucuronide in the Isolated Perfused Rat Liver , Drug Metab. Dispos. 1998, 26, 98 - 104. 

The QSAR data show that glucuronidation can be either a detoxification or bioactivation mechanism, depending chemical structure. For N SAIDs, it appears to be mostly a detoxification mechanism. Nonetheless, the toxicity of acyl glucuronide and glucoside adducts (espedally as it relates to isomerization and protein adduct formation) must be considered when designing carboxylic acids [38]... 

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