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3 Drug‐Metabolism Enzymes and Transporter Activities as Risk Factors of Selected Marketed Drugs Associated with Drug‐Induced Fatalities
Albert P. Li
In vitro ADMET LaboratoriesInc., 9221 Rumsey Road, Suite 8, Columbia, MD, USA
3.1 Introduction
Severe drug toxicity, especially drug‐induced liver toxicity (DILI), is a major challenge in drug development. The occurrence of severe drug toxicity for marketed drugs is a clear indication that the current paradigm for drug safety evaluation during development, namely, preclinical evaluation in multiple species of laboratory animals followed by phases I, II, and III clinical trials, does not always provide adequate information allowing the assessment of human drug safety. The role of metabolism and transport in the toxicity of 12 marketed drugs which have been withdrawn from the market or received black box warning concerning their toxicity are reviewed here to provide evidence of their contribution to drug toxicity. The intent of this chapter is to emphasize the importance of the incorporation of mechanistic studies, at least starting with understanding the role of metabolism and transport in drug toxicity, to hopefully enhance the accuracy of human drug safety evaluation before
