Green trade unions: structure, wages and environmental technology

This paper investigates the effect of trade union structure on firms’ technological choices when unions care about environmental protection. We compare a decentralized with a centralized union structure in a Cournot duopoly. Our results suggest that a decentralized structure provides higher incentives for the investment in cleaner technologies, although emissions may be lower under a centralized structure. The effect of the environmental damage parameter on wages and output may be non-monotonic

The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes

© 2017, Springer International Publishing Switzerland. Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug–drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects. However, the testing of the role of metabolites in CYP inhibition is still not routinely performed during the process of drug development, although the evaluation of time-dependent CYP inhibition during the clinical candidate selection process may provide information on possible effects of metabolites in CYP inhibition. Due to large number of compounds to be tested in the early stages of drug discovery, the experimental approaches fo r assessment of CYP-mediated metabolic profiles are particularly resource demanding. Consequently, a large number of in silico or computational tools have been developed as useful complement to experimental approaches. In summary, circulating metabolites may be recognized as significant CYP inhibitors. Current data may suggest the need for an optimized effort to characterize the inhibitory potential of parent drugs metabolites on CYP, as well as the necessity to develop the advanced in vitro models that would allow a better quantitative predictive value of in vivo studies

Managing the challenge of chemically reactive metabolites in drug development

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This Review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry

Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction

Purpose: To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug-drug interaction (DDI) risk using static mechanistic models. Methods: Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K I and k inact. Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI. Results: Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k inact/K I ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent-drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected. Conclusions: 13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors. © 2012 Springer Science+Business Media, LLC