Drug Bioactivation and Oxidative Stress

Abstract

Adverse drug reactions (ADRs) remain a major complication of drug therapy, account for a significant number of hospital admissions each year and contribute to patient morbidity and mortality. These reactions are a major issue for the pharmaceutical industry, accounting for attrition of approximately one third of compounds in development. Drug toxicity can mimic natural disease and almost any body system can be adversely affected by drugs. However, off‐target or idiosyncratic drug reactions represent a major problem for the pharmaceutical industry because they add significant uncertainty to the process of drug development and can ultimately lead to drug withdrawal or warnings in drug labelling. They are particularly difficult to deal with because they are likely to be discovered late in development or after the drug has been approved; this has important implications as the latter a drug fails, the more expensive is the failure. Excessive dose, drug accumulation and/or the formation of chemically reactive metabolites (CRMs) have been implicated in many ADRs. Such reactions are usually rare and are not evident in animal species, but they can be serious and even fatal in humans and may lead to the withdrawal of otherwise effective therapeutic agents. The fear of such reactions occurring at the post‐approval stage, when such problems typically first become evident is a major impediment to drug development. At present, during preclinical drug evaluation there are no accepted methods for the identification of drugs that may cause hypersensitivity or idiosyncratic drug reactions in humans. The focus of this chapter will be to examine the formation and identification of CRMs through the normal process of phase I and II drug metabolism, elucidate whether these chemically reactive species are toxic, or harmlessly detoxified and excreted and finally to determine if there are any chemical or biological hallmarks of hazard or the development of toxicity, that can be used to more effectively screen out potentially dangerous compounds earlier in the drug development process. This chapter will use case‐study examples of compounds or drugs which have been implicated in a number of off‐target ADRs in humans.

Effect of the interaction between atorvastatin and selective serotonin reuptake inhibitors on the blood redox equilibrium

“…Our previous study carried out on rats treated simultaneously with rosuvastatin and fluoxetine for 14 days revealed a reduction in the TAS (24). This difference may result from the shared metabolism of rosuvastatin and fluoxetine; these drugs are biotransformed by cytochrome P450 isoenzyme CYP2C9, while atorvastatin is metabolized primarily by isoenzyme CYP3A4 (15,21,28). It is also important to note that different durations of treatment were applied (14 days in the previous study, and 28 days in the current study).…”

“…Oxidative stress causes cell damage through a number of mechanisms including lipid peroxidation, protein oxidation, DNA oxidation and mitochondrial damage. This impairment of cellular function can result in cell death and possible organ failure (27,28). However, cells contain antioxidant enzymes that function to maintain the redox status.…”