The Generation, Detection, and Effects of Reactive Drug Metabolites
Identifieur interne : 001113 ( Main/Exploration ); précédent : 001112; suivant : 001114The Generation, Detection, and Effects of Reactive Drug Metabolites
Auteurs : Andrew V. Stachulski [Royaume-Uni] ; Thomas A. Baillie [États-Unis] ; B. Kevin Park [Royaume-Uni] ; R. Scott Obach ; Deepak K. Dalvie ; Dominic P. Williams [Royaume-Uni] ; Abhishek Srivastava [Royaume-Uni] ; Sophie L. Regan [Royaume-Uni] ; Daniel J. Antoine [Royaume-Uni] ; Christopher E. P. Goldring [Royaume-Uni] ; Alvin J. L. Chia [Royaume-Uni] ; Neil R. Kitteringham [Royaume-Uni] ; Laura E. Randle [Royaume-Uni] ; Hayley Callan [Royaume-Uni] ; J. Luis Castrejon [Royaume-Uni] ; John Farrell [Royaume-Uni] ; Dean J. Naisbitt [Royaume-Uni] ; Martin S. Lennard [Royaume-Uni]Source :
- Medicinal Research Reviews [ 0198-6325 ] ; 2013-09.
Abstract
The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein‐reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug–drug interactions that may ensue. One important class of protein‐reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.
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DOI: 10.1002/med.21273
Affiliations:
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Stachulski</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, L69 7ZD, Liverpool</wicri:regionArea><wicri:noRegion>Liverpool</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author><author><name sortKey="Baillie, Thomas A" sort="Baillie, Thomas A" uniqKey="Baillie T" first="Thomas A." last="Baillie">Thomas A. Baillie</name><affiliation wicri:level="4"><orgName type="university">Université de Washington</orgName><country>États-Unis</country><placeName><settlement type="city">Seattle</settlement><region type="state">Washington (État)</region></placeName></affiliation></author><author><name sortKey="Kevin Park, B" sort="Kevin Park, B" uniqKey="Kevin Park B" first="B." last="Kevin Park">B. 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Regan</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Antoine, Daniel J" sort="Antoine, Daniel J" uniqKey="Antoine D" first="Daniel J." last="Antoine">Daniel J. Antoine</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Goldring, Christopher E P" sort="Goldring, Christopher E P" uniqKey="Goldring C" first="Christopher E. P." last="Goldring">Christopher E. P. Goldring</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Chia, Alvin J L" sort="Chia, Alvin J L" uniqKey="Chia A" first="Alvin J. L." last="Chia">Alvin J. L. 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Kitteringham</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Randle, Laura E" sort="Randle, Laura E" uniqKey="Randle L" first="Laura E." last="Randle">Laura E. Randle</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF</wicri:regionArea><wicri:noRegion>Liverpool L3 3AF</wicri:noRegion></affiliation></author><author><name sortKey="Callan, Hayley" sort="Callan, Hayley" uniqKey="Callan H" first="Hayley" last="Callan">Hayley Callan</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Castrejon, J Luis" sort="Castrejon, J Luis" uniqKey="Castrejon J" first="J. Luis" last="Castrejon">J. Luis Castrejon</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Farrell, John" sort="Farrell, John" uniqKey="Farrell J" first="John" last="Farrell">John Farrell</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Naisbitt, Dean J" sort="Naisbitt, Dean J" uniqKey="Naisbitt D" first="Dean J." last="Naisbitt">Dean J. Naisbitt</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE</wicri:regionArea><wicri:noRegion>Liverpool L69 3GE</wicri:noRegion></affiliation></author><author><name sortKey="Lennard, Martin S" sort="Lennard, Martin S" uniqKey="Lennard M" first="Martin S." last="Lennard">Martin S. Lennard</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Academic Unit of Medical Education, University of Sheffield, 85 Wilkinson Street, Sheffield S10 2GJ</wicri:regionArea><wicri:noRegion>Sheffield S10 2GJ</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Medicinal Research Reviews</title><title level="j" type="alt">MEDICINAL RESEARCH REVIEWS</title><idno type="ISSN">0198-6325</idno><idno type="eISSN">1098-1128</idno><imprint><biblScope unit="vol">33</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="985">985</biblScope><biblScope unit="page" to="1080">1080</biblScope><biblScope unit="page-count">96</biblScope><date type="published" when="2013-09">2013-09</date></imprint><idno type="ISSN">0198-6325</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0198-6325</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein‐reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug–drug interactions that may ensue. One important class of protein‐reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Washington (État)</li></region><settlement><li>Seattle</li></settlement><orgName><li>Université de Washington</li></orgName></list><tree><noCountry><name sortKey="Dalvie, Deepak K" sort="Dalvie, Deepak K" uniqKey="Dalvie D" first="Deepak K." last="Dalvie">Deepak K. Dalvie</name><name sortKey="Scott Obach, R" sort="Scott Obach, R" uniqKey="Scott Obach R" first="R." last="Scott Obach">R. Scott Obach</name></noCountry><country name="Royaume-Uni"><noRegion><name sortKey="Stachulski, Andrew V" sort="Stachulski, Andrew V" uniqKey="Stachulski A" first="Andrew V." last="Stachulski">Andrew V. Stachulski</name></noRegion><name sortKey="Antoine, Daniel J" sort="Antoine, Daniel J" uniqKey="Antoine D" first="Daniel J." last="Antoine">Daniel J. Antoine</name><name sortKey="Callan, Hayley" sort="Callan, Hayley" uniqKey="Callan H" first="Hayley" last="Callan">Hayley Callan</name><name sortKey="Castrejon, J Luis" sort="Castrejon, J Luis" uniqKey="Castrejon J" first="J. Luis" last="Castrejon">J. Luis Castrejon</name><name sortKey="Chia, Alvin J L" sort="Chia, Alvin J L" uniqKey="Chia A" first="Alvin J. L." last="Chia">Alvin J. L. Chia</name><name sortKey="Farrell, John" sort="Farrell, John" uniqKey="Farrell J" first="John" last="Farrell">John Farrell</name><name sortKey="Goldring, Christopher E P" sort="Goldring, Christopher E P" uniqKey="Goldring C" first="Christopher E. P." last="Goldring">Christopher E. P. Goldring</name><name sortKey="Kevin Park, B" sort="Kevin Park, B" uniqKey="Kevin Park B" first="B." last="Kevin Park">B. Kevin Park</name><name sortKey="Kitteringham, Neil R" sort="Kitteringham, Neil R" uniqKey="Kitteringham N" first="Neil R." last="Kitteringham">Neil R. Kitteringham</name><name sortKey="Lennard, Martin S" sort="Lennard, Martin S" uniqKey="Lennard M" first="Martin S." last="Lennard">Martin S. Lennard</name><name sortKey="Naisbitt, Dean J" sort="Naisbitt, Dean J" uniqKey="Naisbitt D" first="Dean J." last="Naisbitt">Dean J. Naisbitt</name><name sortKey="Randle, Laura E" sort="Randle, Laura E" uniqKey="Randle L" first="Laura E." last="Randle">Laura E. Randle</name><name sortKey="Regan, Sophie L" sort="Regan, Sophie L" uniqKey="Regan S" first="Sophie L." last="Regan">Sophie L. Regan</name><name sortKey="Srivastava, Abhishek" sort="Srivastava, Abhishek" uniqKey="Srivastava A" first="Abhishek" last="Srivastava">Abhishek Srivastava</name><name sortKey="Stachulski, Andrew V" sort="Stachulski, Andrew V" uniqKey="Stachulski A" first="Andrew V." last="Stachulski">Andrew V. Stachulski</name><name sortKey="Williams, Dominic P" sort="Williams, Dominic P" uniqKey="Williams D" first="Dominic P." last="Williams">Dominic P. Williams</name></country><country name="États-Unis"><region name="Washington (État)"><name sortKey="Baillie, Thomas A" sort="Baillie, Thomas A" uniqKey="Baillie T" first="Thomas A." last="Baillie">Thomas A. Baillie</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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