Acyl glucuronide metabolite

Bolze, S. Bromet, N. Gay-Eeutry, C. Massiere, E Boulieu, R. Hulot, T. Development of an In Vitro Screening Model for the Biosynthesis of Acyl Glucuronide Metabolites and the Assessment of Their Reactivity Toward Human Serum Albumin, Drug Metab. Dispos. 30,404 13 (2002). 

Asif, A. R. et al., Proteins identified as targets of the acyl glucuronide metabolite of mycophenolic acid in kidney tissue from mycophenolate mofetil treated rats, Biochimie, 89 (3), 393, 2007. 

Bolze S, Bromet N, Gay-Feutry C, Massiere F, Boulieu R, Hulot T. Development of an in vitro screening model for the biosynthesis of acyl glucuronide metabolites and the assessment of their reactivity toward human serum albumin. Drug Metab Dispos 2002 30 404-413. 

Sallustio BC, Harkin LA, Mann MC, Krivickas SJ, Burcham PC. Genotoxicity of acyl glucuronide metabolites formed from clofibric acid and gemfibrozil a novel role for phase Il-mediated bioactivation in the hepatocarcinogenidty of the parent aglycones Toxicol Appl Pharmacol 1997 147 459-464. 

A subsequent study by the same authors in 8 kidney transplant patients taking mycophenolate 750 mg to 1 g twice daily found that rifampicin 600 mg daily for 8 days decreased the AUC0.12 and peak levels of mycophenolic acid by 17.5% and 18.5%, respectively. Glucuronide levels were increased and the AUC0.12 and peak levels of the acyl glucuronide metabolite, which has been associated with an increase in mycophenolate adverse effects, was significantly increased by 193% and 121%, respectively. ... 

Meng X, Maggs JL, Pryde DC, Planken S, Jenkins RE, Peak-man TM, Beaumont K, Kohl C, Park BK, Stachulski AV. Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide synthesis, reactivity, and mechanistic analysis. J. Med. Chem. 2007 50 6165-6176. 

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incubations are often carried out at 37 °C for 1-2 h. At different time points, 20-200 /aL of incubation mixture is withdrawn from each incubation and mixed with equal volume of ice-cold acetonitrile by vortexing.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... 

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. 

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... 

However, phase 2 conjugation can also on occasion produce electrophilic intermediates/ metabolites, such as the sulfate conjugation of hydroxytamoxifen (see chap. 7), and the formation of acyl glucuronides with acidic drugs such as diclofenac (Fig. 4.54). 

Peak plasma concentrations are reached within 2 h. Etodolac shows 99 % binding to plasma protein and an elimination half-life of about 7 h (Brooks and Jamali, 1994). Etodolac is metabolized almost completely to the main metabolites 6- or 7-hydroxy-etodolac, acyl-glucuronide, 8-(1 -hydroxyethyl)-etodolac and 4-ureido-etodolac. The metabolites and a small quantity of etodolac are excreted in the urine. A small amount of conjugated etodolac is excreted through the biliary tract. 

The acyl migration of the glucuronide metabolite of the model drug 6,11-dihydro- 11 -oxodibenz (b,e) oxepin-2-acetic acid has also been investigated in urine and pH 7.4 buffer using directly coupled 600 and 750 MHz stop-flow HPLC H NMR spectroscopy [53,54],... 

Disposition in the Body. Readily absorbed after oral administration. Metabolised by side-chain oxidation, glucuronic acid conjugation, and W-dealkylation. Up to about 90% of a dose is excreted in the urine, the major urinary metabolite, probenecid acyl glucuronide, accounting for up to 50% of a dose up to 25% of a dose is excreted as hydroxylated and carboxylic acid... 

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