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6 - Reliability of reactive metabolite and covalent binding assessments in prediction of idiosyncratic drug toxicity

from I - SPECIFIC AREAS OF PREDICTIVE TOXICOLOGY

Published online by Cambridge University Press:  06 December 2010

By
Amit S. Kalgutkar
Edited by
Jinghai J. Xu  and
Laszlo Urban
Jinghai J. Xu
Affiliation:
Merck Research Laboratory, New Jersey
Laszlo Urban
Affiliation:
Novartis Institutes for Biomedical Research, Massachusetts
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Summary

INTRODUCTION

Safety-related attrition continues to be a major concern in the pharmaceutical industry. Of a total of 548 drugs approved in the period from 1975 to 1999, 45 drugs (8.2 percent) acquired 1 or more black box warnings and 16 (2.9 percent) were withdrawn from the market owing to idiosyncratic adverse drug reactions (IADRs) that were not predicted from animal testing and/or clinical trials. IADRs (also known as type B ADRs) are unrelated to known drug pharmacology, and are generally dose-independent. Because the frequency of occurrence of IADRs is very low (1 in 10,000 to 1 in 100,000), these reactions are often not detected until the drug has gained broad exposure in a large patient population. Importantly, standard regulatory animal toxicity studies have traditionally shown a poor concordance with occurrence of IADRs in humans. Life-threatening IADRs noted for drugs include hepatotoxicity, severe cutaneous reactions, aplastic anemia, and blood dyscrasias. Recognizing these issues, many pharmaceutical companies are increasing their efforts in implementing predictive in vitro tools to identify potential safety liabilities earlier in the drug discovery process so that they can be eliminated via chemical intervention or the compound suspended from further development. One component of such assays is aimed at understanding a drug candidate's propensity to undergo reactive metabolite formation.

LINKING METABOLISM WITH TOXICITY

Drugs are metabolized via oxidative, reductive, and hydrolytic pathways (phase I reactions), which lead to a modest increase in aqueous solubility; phase II conjugations modify the newly introduced functionality to form O- and N-glucuronides, sulfate and acetate esters, all with increased hydrophilicity relative to the unconjugated metabolite.

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Predictive Toxicology in Drug Safety , pp. 102 - 123
Publisher: Cambridge University Press
Print publication year: 2010

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