Acyl glucuronides: the good, the bad and the ugly

Abstract

Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

“…3; Table 6), two nonsteroidal anti-inflammatory drugs that are commonly administered both topically and orally. Because acyl glucuronides may be chemically reactive (Regan et al, 2010;Boelsterli and Ramirez-Alcantara, 2011;Dickinson, 2011), this finding has potential implications for skin toxicity, such as skin rash, an adverse effect observed for numerous therapeutic drugs (Mayorga et al, 2009;Chanprapaph et al, 2014). A more recent study also reported that the formation of 12-hydroxynevirapine sulfate induced skin rash in rats (Sharma et al, 2013).…”

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

“…Acyl glucuronides, which are enzymatic products formed by glucuronidation of carboxylic acids (Stachulski et al, 2006), are capable of undergoing the following: 1) hydrolysis to parent aglycone mediated by b-glucuronidases, nonspecific esterases, hydroxyl ion, or serum albumin; 2) intramolecular acyl migration to form positional isomers that are resistant to b-glucuronidase-mediated hydrolysis; and 3) covalent binding to proteins via transacylation or glycation mechanisms (Regan et al, 2010). Acyl glucuronides, however, differ widely in their chemical reactivity, which is attributed to the chemical structure of the aglycone moiety (Stachulski et al, 2006).…”

Analytical Methods for Quantification of Drug Metabolites in Biological Samples

“…N-glucuronides (primary, secondary and N-hydroxylated amines) are hydrolyzed under mild acidic conditions but quartenary ammonium glucuronides under basic conditions [25]. Additionally, enzymatic hydrolysis of acyl glucuronides may be hindered due to acyl migration what leads to ß-glucuronidase resistant derivates [59]. Nevertheless, if the ß-glucuronidase treatment is successful for the metabolite of interest, this procedure should be the method of choice.…”

“…Different acyl glucuronides have been shown to have different rates of hydrolysis. However, mildly acidic conditions (pH 3-5) should be the most desirable pH for minimizing the reaction in biological samples [59,111]. Acyl glucuronides (1-O-acyl glucuronides) are also susceptible to internal migration under both, physiological and alkaline conditions.…”