Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism

Abstract

It is now widely appreciated that drug metabolites, in addition to the parent drugs themselves, can mediate the serious adverse effects exhibited by some new therapeutic agents, and as a result, there has been heightened interest in the field of drug metabolism from researchers in academia, the pharmaceutical industry, and regulatory agencies. Much progress has been made in recent years in understanding mechanisms of toxicities caused by drug metabolites, and in understanding the numerous factors that influence individual exposure to products of drug biotransformation. This review addresses some of these factors, including the role of drug-drug interactions, reactive metabolite formation, individual susceptibility, and species differences in drug disposition caused by genetic polymorphisms in drug-metabolizing enzymes. Examples are provided of adverse reactions that are linked to drug metabolism, and the mechanisms underlying variability in toxic response are discussed. Finally, some future directions for research in this field are highlighted in the context of the discovery and development of new therapeutic agents.

Figure 1

Pathways of metabolism of acetaminophen (APAP), indicating the proposed role of metabolic activation to NAPQI in APAP-mediated liver injury.

Figure 2

Drugs which serve as precursors of quinone imine formation. In one case (amodiaquine), the p-aminophenol moiety is present in the parent compound, whereas in the other examples, metabolic oxidation (at the indicated sites) is required to introduce this structural feature.

Figure 3

Metabolic activation of heteroatom-substituted benzene derivatives to reactive “quinoid” intermediates that can covalently modify proteins and/or cause oxidative stress. For the pathway leading to reactive oxygen species, X = oxygen or nitrogen, and Y = oxygen.

Figure 4

Oxidation of terfenadine to its active carboxylic acid metabolite fexofenadine, and inhibition of this pathway by inhibitors of CYP3A4.

Figure 5

Oxidative bioactivation of 4-ipomeanol to a reactive ene-dial species.

Figure 6

Proposed pathway for the metabolism of efavirenz to a nephrotoxic metabolite(s), which is believed to result from activation of the cysteine conjugate, either through S-oxidation.

Figure 7

Candidate gene analaysis of potential pathways of diclofenace bioactivation (70).