Glucuronides, ester

Ester glucuronides are somewhat chemically reactive and can covalently bind to protein. It has been proposed that this type of metabolite is responsible for the idiosyncratic reactions associated with several drugs that are carboxylic acids as discussed in Chapter 8. 

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... 

Figure 4.50 Formation of ether and ester glucuronides of phenol and benzoic acid, respectively.

Structural details of both are discussed by Bray.4 In the literature, type III has often been called an ether glucuronide and the type shown in IV has been called an ester glucuronide. ... 

Over 70% of a lethal dose of eugenol was recovered from the urine of rabbits after death. The administration of single 200 mg doses to rats was also reported to increase urinary output of ethereal glucuronides of 33-35 mg/rat in 12 hours compared to the control value of 4 mg/rat. Ester glucuronide values were unchanged. Subcutaneous injection of 0.1 mL of purified eugenol in adult Walter Reed white rats caused necrosis and inflammation at the injection site [29-33]. 

Tremaine LM, Stroll JG, Ronfeld RA. Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline. Drug Metab Dispos 1989 17 58-63. 

UDP-Glucuronic Acid Benzoic Acid Ester Glucuronide... 

Although this is a reversible reaction in vitro, the carboxylic acids formed are either converted rapidly to their ester glucuronide derivatives (a phase II reaction catalyzed by UDP-glucuronosyltransferase see below) or, if polar enough, are excreted unchanged. Consequently, the reverse reaction is generally not of significance in vivo. 

Certain jS-glucuronides are electrophilic in nature and may also function in toxication processes. Covalent binding of the aglycone portions of several carboxylic acid (ester) glucuronides is known to occur to nucleophilic sites on serum albumin via transacylation reactions, for example. 

BHT is cleared less rapidly from most species, enterohepatic circulation being partly responsible for the delay. The major metabolites of BHT in rat urine are 3,5-di-Tbutyl-4-hydroxybenzoic acid (BHT acid III), both free (90% of the dose) and as a glucuronide (15%), and S-(3,5-di-Tbutyl-4-hydroxybenzyl)-N-acetylcysteine. The ester glucuronide and mer-capturic acid were major metabolites in rat bile, while free BHT acid was the main component in the feces. In addition, l,2-bis(3,5-di- -butyl-4-hydroxy-phenyl) ethane has been identified in rat bile. In BALB/c mice, 75% of a single oral dose was excreted in the urine during the first 24 h this was followed by a slower phase during which an additional 10% was excreted over the next 4 days. The total amount found in the feces was less than 1%. Female rats have greater urinary excretion of BHT than male rats, whereas male BALB/c mice excreted BHT more rapidly than females. 

LC/MS has had a strong influence upon pharmaceutical chemistry for the analysis of both highly polar metabolites and their precursors, as described in the second section of this book. The technique has been used for the analysis of polypeptides and a variety of intractable pharmaceuticals such as tetracycline, -lactams, and polyether antibiotics. The structures of highly polar drug metabolites formed in vivo— including sulfate esters, glucuronides, taurine, and camotine... 

RG Dickinson, WD Hooper, MJ Eadie. pH Dependent rearrangement of the biosynthetic ester glucuronide of valproic acid to beta-glucuronidase-resistant forms. Drug Metab Dispos 12(2) 247—252, 1984. 

Many drugs containing carboxylate groups form /3-1-O-acyl glucuronides as major metabolites. Such ester glucuronides are potentially reactive due to the... 

In rat, dibenzylether is split with subsequent oxidation to corresp. benzoic acid (M) and its ester glucuronide (M), Intermediate aldehyde also found (m) (31). 

M Tanaka, K Ono, H Hakusui, T Takegoshi, Y Watanabe, M Kanao. Identification of DP-1904 and its ester glucuronide in human urine and determination of their enantiomeric compositions by high-performance liquid chromatography with optical activity and ultraviolet detection. Drug Metab Dispos 18 698, 1990. 

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