TY - JOUR
T1 - The generation, detection, and effects of reactive drug metabolites
AU - Stachulski, Andrew V.
AU - Baillie, Thomas A.
AU - Kevin Park, B.
AU - Scott Obach, R.
AU - Dalvie, Deepak K.
AU - Williams, Dominic P.
AU - Srivastava, Abhishek
AU - Regan, Sophie L.
AU - Antoine, Daniel J.
AU - Goldring, Christopher E.P.
AU - Chia, Alvin J.L.
AU - Kitteringham, Neil R.
AU - Randle, Laura E.
AU - Callan, Hayley
AU - Castrejon, J. Luis
AU - Farrell, John
AU - Naisbitt, Dean J.
AU - Lennard, Martin S.
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - Acyl glucuronides
KW - Covalent binding
KW - Cytochromes P-450
KW - Drug design
KW - Drug-drug interactions
KW - Drug-induced toxicity
KW - Enzyme inhibition
KW - Immunology
KW - Reactive drug metabolites
UR - http://www.scopus.com/inward/record.url?scp=84881234547&partnerID=8YFLogxK
U2 - 10.1002/med.21273
DO - 10.1002/med.21273
M3 - Artículo
SN - 0198-6325
VL - 33
SP - 985
EP - 1080
JO - Medicinal Research Reviews
JF - Medicinal Research Reviews
IS - 5
ER -