Role of Bioactivation in Idiosyncratic Drug Toxicity: Structure–Toxicity Relationships

Adverse drug reactions (ADRs) continue to be a significant contributor to overall attrition statistics in the pharmaceutical industry. ADRs pose a significant health problem since they contribute to patient morbidity and mortality and represent one of the most common causes for pharmaceutical product recalls and black-box warning labels. Of a total of 548 drugs approved in the period from 1975 to 1999, 45 drugs (8.2%) acquired one or more black-box warnings and 16 (2.9%) were withdrawn from the market (Lasser et al. 2002). An estimated 100 000 fatalities annually are attributed to ADRs making it the fourth to sixth leading cause of death in the United States (Lazarou, Pomeranz and Corey 1998). Therefore, increased emphasis has been placed on the identification of indicators of ADRs in preclinical species and humans as early as possible in the overall discovery/ development process. Adverse drug reactions can be classified into two categories namely type A and type B reactions. Type A or augmented reactions account for approximately 80% of all ADRs and are predictable from the known primary or secondary pharmacology of the drug. They show simple dose–response relationships and, therefore, can be usually avoided by dose reduction and are rarely life-threatening. Type A ADRs can be routinely identified in preclinical toxicological investigations. Typical examples of type A ADRs include the risk of hypotension with antihypertensives and hemorrhage with anticoagulants. Currently, risk assessment of overall toxicity in the clinic is usually based on the safety margin of the drug candidate, which is often the ratio of the no observable adverse effect