Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic Glutathione<i>S</i>-Transferases

Osbild, Sandra; Bour, Jérome; Maunit, Benoı̂t; Guillaume, Cécile; Asensio, Carine; Müller, Jean-François; Netter, Patrick; Kirsch, Gilbert; Bagrel, Denyse; Lapicque, Françoise; Battaglia, Eric

doi:10.1124/dmd.107.016808

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…NSAIDs can be metabolized to their acyl glucuronides and CoA-derivatives. [45][46][47] These CoA-derivatives are suspected to contribute to the adverse effects through their binding to macromolecules. If monoterpenoid alcohols suppress the formation of acyl glucuronides, this would lead to the compensatory production of acyl-CoA derivatives.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Ishii

Iida

Miyauchi

et al. 2012

Biological & Pharmaceutical Bulletin

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Morphine is an important drug used to alleviate moderate to severe pain. This opiate is mainly metabolized by glucuronidation to a non-analgesic metabolite, morphine-3-glucuronide (M-3-G) and an active metabolite morphine-6-glucuronide (M-6-G). To understand the modulation of morphine glucuronidation activity by environmental factors, the effect of endogenous and food-derived compounds on morphine uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) in rat and human microsomes was evaluated examining the 50% inhibitory concentration (IC 50 ). The liver microsomes from Sprague-Dawley rats (RLM) and humans (HLM, 150 donors, pooled microsomes) were used as enzyme sources. Of 27 compounds tested, monoterpenoid alcohols, such as borneol and iso-borneol, exhibited a strong inhibitory effect on morphine glucuronidation in rat liver microsomes (RLM), whereas we failed to detect any inhibitory effect of endogenous substances including amino acids and sugars. The substances which have the ability to inhibit the activity in RLM are also inhibitory toward morphine glucuronidation in HLM and UGT2B7 baculosomes. However, the difference was that while the strongest inhibitory effect was observed for iso-menthol in HLM, borneol was the strongest inhibitor of the activity mediated by RLM. Although zidovudine is a typical substrate of UGT2B7, the inhibition of morphine glucuronidation by zidovudine was far weaker than that of monoterpenoid alcohols. These results demonstrate that dietary and supplementary monoterpenoid alcohols modify the pharmacokinetics and pharmacodynamics of morphine through inhibition of UGT2B7.Key words uridine 5′-diphosphate-glucuronosyltransferase; glucuronidation; morphine; borneol; iso-menthol; monoterpenoid alcohol Morphine is an important analgesic for relieving moderate to severe pain (WHO). The major metabolic pathway for morphine is glucuronidation leading to the formation of morphine-3-glucuronide (M-3-G) and morphine-6-glcuronide (M-6-G).1) While M-3-G is a non-analgesic metabolite, M-6-G is a far more potent analgesic than the parent morphine.2) M-3-G is the major metabolite of morphine in many species. However, the ability to form M-6-G varies from species to species, 3) and relatively higher activity was detected in humans 4,5) and guinea pigs.3) Glucuronidation is catalyzed by uridine 5′-diphosphate (UDP)-glucuronosyltrasferase (UGT) which is expressed mainly in the liver and gastro-intestinal tract.6) UGT is a family of enzymes which transfer the glucuronic acid moiety of the co-substrate, UDP-glucuronic acid (UDPGA), to an acceptor substrate.7) Previous studies have suggested that, among UGT isoforms, UGT2B1 and UGT2B7 contribute to morphine glucuronidation in rats and humans, respectively. 8,9)The accelerated action of narcotics is recommended for curing cancer pain because withdrawal symptoms rarely happen even following the opiate treatment of patients with pain.10) However, a problem associated with the clinical use of narcotics is that the mortality of patients due to overdosing ...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Ishii

Iida

Miyauchi

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Acyl-CoA metabolites of several NSAIDs including zomepirac ( 15 ) have been detected in vitro and in vivo . − Acyl-CoA derivatives of carboxylic acid drugs act as intermediates in a number of phase II conjugation reactions, including amino acid conjugation. As such, the intermediate acyl CoA metabolites of carboxylic acids are thioester derivatives, which possess sufficient electrophilicity toward nucleophilic reactions with amino acid residues on proteins as well as with GSH (Scheme ). − For instance, the hypolipidemic drug nafenopin (see Scheme ) was shown to transacylate liver proteins following in vitro incubations with liver homogenates, resulting in amide and thioester linkages with protein lysine and cysteine amino acid residues, respectively, and to linearly correlate the plasma AUC of nafenopin protein acylation with the AUC of nafenopin-CoA formation . As was noted with acyl glucuronides, the substitution pattern around the acyl CoA metabolites greatly influences chemical reactivity; increasing substitution at the α-carbon generally correlates with a decrease in reactivity with nucleophiles …”

Section: Structural Alert and Rm Analyses For Drugs Recalled Due To I...mentioning

confidence: 99%

Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States

Stepan

Walker

Bauman

et al. 2011

Chem. Res. Toxicol.

593

686

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Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (∼78-86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochemical properties such as molecular weight, lipophilicity, etc. Approximately half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chemical architecture, and many were found to be RM-positive. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-positive drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity ...

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“…Besides bioactivation via the acyl glucuronide route, carboxylic acid-containing drugs can also undergo metabolism to electrophilic acyl-coenzyme A thioesters (acyl-CoAs) (e.g., compound 26 ), which possess higher reactivity (∼40–70 times greater) than acyl glucuronides toward covalent interactions with hepatic proteins, and can also react with GSH to yield thiol adducts such as 27 (Scheme ). ,,− In recent work, Darnell et al demonstrated that the reactivities of the CoA conjugates of seven radiolabeled NSAIDs including 19 and 20 were much higher compared with those of their corresponding acyl glucuronide and oxidative metabolites, as estimated from the degree of covalent binding to human liver microsomal protein. Interestingly, all seven NSAIDs formed acyl glucuronide metabolites in abundant quantities in uridine 5′-diphosphoglucuronic acid (UDPGA)-supplemented human liver microsomes, but none of them demonstrated covalent binding to liver microsomes containing UDPGA.…”

Section: The Structural Alert Conceptmentioning

confidence: 99%

Designing around Structural Alerts in Drug Discovery

Kalgutkar

2019

J. Med. Chem.

117

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Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds.Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure−metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/ reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.

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Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic GlutathioneS-Transferases

Cited by 7 publications

References 40 publications

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States

Designing around Structural Alerts in Drug Discovery

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