Toxicity idiosyncratic

Williams DP, Park BK. Idiosyncratic toxicity the role of toxicophores and bioactivation. Drug Discov Today 2003 8 1044-50. 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

Trepanier, L.A., Idiosyncratic toxicity associated with potentiated sulfonamides in the dog. J. Vet. Pharmacol. Ther., 27, 129, 2004. 

If there is high confidence that the dose will be low either because of the dose route (e.g., inhaled) or because the target is precedented and similar molecules are known to work at a low dose or exposure, then this is sufficient to proceed at risk to candidate selection since the incidence of idiosyncratic toxicity decreases considerably with dose and few if any examples are present for compounds dosed at 10 mg or less in human. If however a high dose is predicted or there is considerable uncertainty in the prediction then some evaluation of CB risk should be made. 

Reactive metabolite screen Reactive metabolites have been increasingly implicated in idiosyncratic toxicity... 

Cribb, A.E. et al. (1991) Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity. Drug Metabolism and Disposition The Biological Fate of Chemicals, 19 (5), 900-906. 

Ulrich, R.G. (2007) Idiosyncratic toxicity a convergence of risk factors. Annual Review of Medicine, 58, 17-34. 

As with carbamazepine, phenytoin also causes idiosyncratic toxic effects, including hematological and connective tissue toxicities, hepatotoxicity, and teratogenicity (89). Although some of these toxicities have been hypothesized to be caused by P450 oxidative metabolism (92,93) or peroxidase-mediated reactions (94,95), mechanisms for these toxic effects in humans are unknown. 

Idiosyncratic toxicity Metabolic abnormality No No Weeks-months Any Increased liver enzymes, hepatitis, jaundice Diclofenac Ketoconazole... 

Idiosyncratic toxicity Immunoallergic reaction No No 1-5 weeks Any Fever, rash, eosinophilia, arthralgias, hepatitis Halothane Carbamazepine... 

Shear NH, Spielberg SP, Grant DM, Tang BK, Kalow W. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986 105(2) 179-84. 

The idiosyncratic toxicity, manifested by neurological effects, shown by a subpopulation of (rough-haired) Collies to ivermectin (> 100 gg/kg, p.o.) may be attributed to a breed-related compromised blood-brain barrier (Tranquilli et al, 1989), since y-aminobutyric acid receptors that mediate neurotransmission are confined to the CNS in mammalian species. The pharmacokinetic behaviour of ivermectin does not differ between ivermectin-sensitive and... 

When the toxicity is dose-responsive (either as chemistry- or mechanism-based) the toxicity can be correlated with the exposure of the toxic chemical species, in the right compartment for the sufficient time to cause toxicity. When the toxicity is not dose-responsive, an inquiry ensues to discover what makes an affected individual more susceptible. This is the case in idiosyncratic toxicity in humans. 

The mechanism of action of the enzymes is a complex multistep process that leads to the biotransformation of substrate, most often to an oxidized product.28-30 The process of oxidation involves high-energy intermediates and often involves the generation of reactive electrophilic intermediates at the enzyme active site that are sometimes released and can react with cellular components.31-35 This process is thought to contribute to the acute or idiosyncratic toxicity displayed by some compounds.32-34... 

The reaction of N-oxygenated drugs and metabolites with glutathione may also have toxicological and medicinal implications. Thus, the addition of GSH to nitrosoarenes, probably followed by rearrangement, forms sulfinamides (reaction 9), which have been postulated to contribute to the idiosyncratic toxicity of a few drugs such as sulfonamides... 

A further consideration in aiming to predict drug interaction in humans is to ask which human The variation in the human genome may help to explain the many, well-catalogued examples of idiosyncratic toxicity. Genetic, physiological and... 

Including this toxicity in the area of idiosyncratic toxicity is justified since the lung is not thought of a typical target for cytotoxic chemotherapy. Rather, the toxicity results from an unexpected organ differential that results in an unexpected but not rare toxicity. Further, there are few indicators that will provide insight into if and when this toxicity will be encountered. 

To address this organ-directed idiosyncratic toxicity we will highlight two drugs, cisplatin and streptomycin, which are chemically distinct (see structure in Figure 13.8) yet have an intriguing similarity of spectrum of activities. 

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