Covalent binding drug toxicity

GILLETTE, J.R. (1973) Factors that effect the covalent binding and toxicity of drugs. In... 

Fan PW, Bolton JL (2001) Bioactivation of tamoxifen to metabolite E quinone methide reaction with glutathione and DNA. Drug Metab Dispos 29 891-896 Fischer V, Haar JA, Greiner L et al (1991) Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis. Mol Pharmacol 40 846-853 Fisher R, Brendel K, Hanzlik RP (1993) Correlation of metabolism, covalent binding and toxicity for a series of bromobenzene derivatives using rat liver slices in vitro. Chem Biol Interact 88 191-198... 

Nakayama, S., Atsumi, R., Takakusa, H., Kobayashi, Y, Kurihara, A., Nagai, Y, Naiai, D., Okazaki, O. (2009). A zone classification system for risk assessment of idiosyncratic dmg toxicity using daily dose and covalent binding. Drug Metabolism and Disposition, 37, 1970-1977. 

Zhou, S., Chan, E., Duan, W. et al. (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metabolism Reviews, 1, 41-213. 

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. 

It is tempting, given the above, to conclude that any degree of covalent binding of drug species to macromolecules will lead to a toxic response. However, this is clearly not the case as there are plenty of examples where covalent binding has had no toxicological consequence. 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

Takakusa, H., Masumoto, H., Yukinaga, H., Makino, C., Nakayama, S., Okazaki, O. and Sudo, K. (2008) Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36 (9), 1770-1779. 

Leone, A.M. et al. (2007) Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression. Chemical Research in Toxicology, 20 (4), 600-608. 

Chapter 7. Gorrod, J. W. Covalent binding as an indication of drug toxicity. 

The principal mechanisms underlying the primary events of drug toxicity include (1) covalent binding, (2) lipid peroxidation, and (3) oxidative stress. The dividing line between these types of mechanisms is not always clear. For example, a reactive intermediate may cause death via covalent binding while the necrotic cells may release toxic oxidative products. The reverse scenario is also conceivable. 

With the exception of some anticancer drugs, chemicals directly toxic to tissues are eliminated in the drug development process, so drug toxicity involving covalent binding usually is mediated by chemically reactive metabolites. Current mechanistic understanding of these toxic reactions usually extends to identification of the reactive metabolite and metabolic pathway involved. In some cases, protective mechanisms for... 

The binding of drug to tissue is usually reversible. In some cases, however, there is covalent binding, which by definition is not reversible. This applies to drug or metabolite and could be important because it could be related to toxicity. " A good correlation has been reported in animals between the degree of covalent binding to hepatic protein and the severity of hepatic necrosis of paracetamol, isoniazid, adriamycin, and furosemide. " ... 

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