Selection of new chemical entities with decreased potential for adverse drug reactions

Park, Kevin B.; Dalton-Brown, Emma; Hirst, Charlotte; Williams, Dominic P.

doi:10.1016/j.ejphar.2006.08.025

Cited by 37 publications

(17 citation statements)

References 53 publications

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“…Lapatinib has an acceptable safety profile for its therapeutic indication; however, hepatotoxicity (ALT or aspartate transaminase Ͼ3 times the upper limit of normal and total bilirubin Ͼ2 times the upper limit of normal) has been observed in clinical trials (Ͻ1% of patients) and postmarketing experience (GlaxoSmithKline, Tykerb product information, 2007, http://us.gsk.com/products/assets/us_tykerb.pdf). Recent advances in molecular toxicology have established a basis for understanding the mechanisms of hepatotoxins at the chemical and cellular levels with drug metabolism studies providing a logical framework to link in vitro and whole animal studies to man (Park et al, 2006). Thus, understanding the metabolism and distribution of lapatinib in humans provides a platform to investigate the origins of hepatotoxicity and hypothesis building.…”

Section: Discussionmentioning

confidence: 99%

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Castellino

O'Mara²,

Koch³

et al. 2011

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 99%

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Castellino

O'Mara²,

Koch³

et al. 2011

Drug Metab Dispos

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“…Nevertheless, a large number of drugs that have been removed from the market (or have been labeled with a “black‐box” warning) due to safety concerns have been shown to undergo metabolic activation, suggesting that reactive metabolite formation, while not a reliable predictor of drug toxicity in humans, represents a significant risk factor in drug development . In that context, most major pharmaceutical companies have adopted approaches to detect and identify reactive metabolites from new chemical entities during the lead optimization phase of drug discovery in an effort to design analogs that are less susceptible to bioactivation . By this means, those molecules ultimately selected for entry into development should have a lower probability of causing toxicities that are frequently associated with CRMs, viz., hepatotoxicity, skin reactions, and blood dyscrasias .…”

Section: Introductionmentioning

confidence: 99%

The Generation, Detection, and Effects of Reactive Drug Metabolites

et al. 2012

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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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“…However, there is general agreement that the exposure of cells to reactive, electrophilic metabolites of foreign compounds is an undesirable outcome (4, 5), and most major pharmaceutical companies now have established procedures to detect such short-lived intermediates through appropriate in Vitro and in ViVo studies and, by way of appropriate structural modifications to lead compounds, divert metabolism to pathways that yield chemically stable products (6)(7)(8). In the past two decades, genetic aspects of both drug metabolism and susceptibility to drug toxicity have become widely appreciated, and reaction phenotyping (primarily with regard to human drug-metabolizing enzymes that exhibit genetic polymorphism, for example, CYP2D6 and 2C19) now is a standard component of the in Vitro profiling of all drug candidates entering development.…”

Section: The Past 20 Yearsmentioning

confidence: 99%

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

Baillie

2007

Chem. Res. Toxicol.

188

116

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The science of drug metabolism and pharmacokinetics (DMPK) has developed significantly over the past 20 years, and its functional role in today's pharmaceutical industry has matured to the point where DMPK has become an indispensable discipline in support of drug discovery and development. While contributions to the lead optimization phase of discovery efforts have been particularly noteworthy in helping to select only the best drug candidates for entry into development, it should be recognized that the scope of DMPK spans the continuum of discovery through clinical evaluation and even into the post-marketing phase; as such, the breadth of DMPK's involvement is almost unique in contemporary pharmaceutical research. This perspective summarizes notable advances in the field, many of which have been made possible by technological developments in areas such as molecular biology, genetics, and bioanalytical chemistry, and highlights the critical nature of key partnerships between Drug Metabolism, Medicinal Chemistry, and Safety Assessment groups in attempting to advance drug candidates with a low potential for causing adverse events in humans. Finally, some speculative predictions are made of the future role of DMPK in pharmaceutical research, where current advances in our mechanistic understanding of the molecular processes that control the absorption, disposition, metabolism, elimination, and toxicity of drugs and their biotransformation products will combine to further enhance the impact of DMPK in drug discovery and development.

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Selection of new chemical entities with decreased potential for adverse drug reactions

Cited by 37 publications

References 53 publications

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

The Generation, Detection, and Effects of Reactive Drug Metabolites

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

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