Evaluation of Metabolism-Dependent Drug Toxicity

Drug metabolism is well-established to play key roles in drug toxicity. Drug toxicity can be enhanced via biotransformation of a parent drug to metabolites with a higher toxicity potential, a process known as bioactivation. Conversely, a toxic drug can be biotransformed to a less toxic metabolite, a process known as detoxification. In drug development, it is critical to define the roles of drug metabolism in the toxic potential of drug candidates. A drug candidate where drug metabolism plays a key role in the toxic potential may have serious complications in a safety assessment which includes the following: (1) Preclinical safety trials may not accurately reflect human safety due to species difference in drug metabolism; (2) Individual differences in drug metabolism may result in the occurrence of idiosyncratic drug toxicities which, due to the low incidence, may not be readily detected in regulatory clinical trials, but may be manifested post marketing upon exposure to a large patient population, resulting in market withdrawal or severe limitation of usage by regulatory agencies. In this chapter, in vitro experimental systems to define the roles of human-specific drug metabolism on drug toxicity are described. These experimental systems may be applied in drug development for candidate selection to minimize safety liabilities.