Hepatic covalent adduct formation with zomepirac in the CD26‐deficient mouse

Wang, Min; Gorrell, Mark D.; Abbott, Catherine A.; Jaggi, Rene; Marguet, Didier; Dickinson, R. G.

doi:10.1046/j.1440-1746.2002.02662.x

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…Using TR-rats, deficient in the transporter Mrp2, which transports glucuronides across the canalicular membrane, they were able to show that when diclofenac-glucuronide transport into the bile was absent, no formation of the 118 kDa adduct was seen, thus demonstrating the need for biliary transport of the glucuronides, and subsequent increased concentration of diclofenac-glucuronide in bile [82] . Similar covalent binding to DPP IV has been shown for zomepirac [83,84] and benoxaprofen [73] .…”

Section: Consequences Of Chemical Reactivity Of Carboxylic Acid Metabsupporting

confidence: 69%

Metabolic activation of carboxylic acids

Skonberg

Olsen

Madsen

et al. 2008

Expert Opinion on Drug Metabolism & Toxicology

139

114

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Background : Carboxylic acids constitute a large and heterogeneous class of both endogenous and xenobiotic compounds. A number of carboxylic acid drugs have been associated with adverse reactions, linked to the metabolic activation of the carboxylic acid moiety of the compounds, i.e., formation of acyl-glucuronides and acyl-CoA thioesters. Objective : The objective is to give an overview of the current knowledge on metabolic activation of carboxylic acids and how such metabolites may play a role in adverse reactions and toxicity. Methods : Literature concerning the formation and disposition of acyl glucuronides and acyl-CoA thioesters was searched. Also included were papers on the chemical reactivity of acyl glutathionethioesters, and literature concerning possible links between metabolic activation of carboxylic acids and reported cellular and clinical effects. Results/conclusion : This review demonstrates that metabolites of carboxylic acid drugs must be considered chemically reactive, and that the current knowledge about metabolic activation of this compound class can be a good starting-point for further studies on the consequences of chemically reactive metabolites.

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Section: Consequences Of Chemical Reactivity Of Carboxylic Acid Metabsupporting

confidence: 69%

Metabolic activation of carboxylic acids

Skonberg

Olsen

Madsen

et al. 2008

Expert Opinion on Drug Metabolism & Toxicology

139

114

View full text Add to dashboard Cite

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“…Like those of diclofenac, these included adducts of DPPIV, a glycoprotein expressed on the bile canalicular surface, and their formation was apparently mediated through biliary excretion of zomepirac acyl glucuronide 181. Further evidence for the role of DPPIV in zomepirac adduct formation comes from studies on the CD‐26 deficient mouse 182. Depletion of DPPIV (CD26) from deficient mice decreased levels of adduct formation.…”

Section: The Inherent Reactivity Of Acyl Glucuronidesmentioning

confidence: 99%

“…Depletion of DPPIV (CD26) from deficient mice decreased levels of adduct formation. The detection of residual zomepirac adducts in the CD‐26 deficient mouse suggested that proteins of a similar molecular weight to DPPIV may also be targets for zomepirac adduction 182. Antibody methods do not provide conclusive proof that adducts are formed from acyl glucuronide metabolites, as they only recognise the parent drug residue, and, as with tolmetin, zomepirac forms oxidised metabolites which may themselves modify proteins 183–185.…”

Section: The Inherent Reactivity Of Acyl Glucuronidesmentioning

confidence: 99%

Acyl glucuronides: the good, the bad and the ugly

Regan

Maggs

Hammond

et al. 2010

Biopharm & Drug Disp

166

145

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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.

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“…Both ZP and TM acyl glucuronides have been shown to be capable of covalently modifying proteins via the glycation mechanism (Smith et al, 1986(Smith et al, , 1990Hyneck et al, 1988). Target proteins for modification include plasma albumin in humans, tubulin and dipeptidyl peptidase IV in rats, and CD26 in mice (Bailey et al, 1998;Wang et al, 2001Wang et al, , 2002. As a result, the reactive acyl glucuronides of ZP and TM have been hypothesized to serve as mediators of the serious adverse effects of these drugs (Zia-Amirhosseini et al, 1995).…”

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confidence: 99%