Reactive metabolites formation

Reactive Metabolite Formation, Mechanism-Based CYP Inhibition,... 

Mansuy D, Valadon P, Erdelmeier I, et al. Thiophene S-oxides as new reactive metabolites formation by cytochrome P450 dependent oxidation and reaction with nucleophiles. J Am Chem Soc 1991 113(20) 7825—7826. 

Ju, C. andUetrecht, J.P. (2002) Mechanism of idiosyncratic drug reactions reactive metabolites formation, protein binding and the regulation of the immune system. Current Drug Metabolism, 3, 367-377. 

While covalent binding studies have an advantage over the reactive metabolite assay in that they provide a quantitative estimate of covalently bound drug to proteins and therefore an indirect measure of reactive metabolite formation, there are no studies to date which show a correlation between the extent of covalent binding and/or reactive metabolite formed and the probability that a drug is... 

Pearson, P.G., Omichinski, J.G., McClanahan, R.H., Soderlund, E.J., Dybing, E. Nelson, S.D. (1993a) Metabolic activation of tris(2,3-dibromopropyl) phosphate to reactive intermediates. 1. Covalent binding and reactive metabolite formation in vitro. Toxicol, appl. Pharmacol., 118, 186-195... 

Kalyanaraman N. Inhibition of naltrexone metabolism by NSAIDs leading to metabolic switching and reactive metabolite formation. In MS. thesis. Minneapolis University of Minnesota, 2004. 

Lopez Garcia, M. P. Dansette, P. M. Valadon, P. Amar, C. Beaune, P. H. Guengerich, E. P. Mansuy, D. Human-liver cytochrome P-450 expressed in yeast as tools for reactive-metabolite formation studies Oxidative activation of tienilic add by cytochromes P-450 2C9 and 2C10, Eur. J. Biochem., 1993, 213, 223-232. 

These reactions are not generally thought of as dose related. However, mass action law considerations dictate that the extent of reactive metabolite formation, and hence adverse reaction risk, will also be a function of drug dosage. It also can be inferred from Figure 16.4 that part of the interindividual... 

Tune B.The nephrotoxicity of cephalosporin antibiotics. Sturcture-activity relationship. Commun Toxicol 1993 1 145-157. Pearson PG, Omichinski JG, Flolme JA, McClanahan REI, Brunborg G, Soderlund EJ, Dybing E, Nelson SD Metabolic activation of tris (2,3, dibromopropyl) phosphate to reactive intermediates Covalent binding, reactive metabolite formation and differential metabolite-specific DNA damage, n v Vo.Toxicol AppI Pharmacol 1993 118 186-196. 

In a more thorough and balanced evaluation of the in vitro reactive metabolite tests in both human liver microsomes and S9 fractions, Obach et al. found that a panel of safe drugs in the clinic can form as much reactive metabolites as those hepatotoxic drugs, even after corrections for drug clearance parameters.92-93 Obviously, a more balanced and system-based approach to reactive metabolite formation and its clinical implications is needed hence forward. 

Experimental methodology to evaluate reactive metabolite formation... 

To date, there are no examples where in silico tools have been utilized in a proactive fashion to predict reactive metabolite formation with small molecules. There are virtual or experimental techniques that can predict metabolic outcomes including the potential for forming reactive metabolites to some degree or the other. At best, these techniques have been used to rationalize published experimental observations on bioactivation pathways. Exploitation of these tools in drug discovery in a proactive fashion would necessitate additional experimental studies to validate the predictions. 

Figure 6-3 Examples of drugs evaluated for reactive metabolite formation via electrochemical...

A second example is evident from the work of Singh et al.68 on the pyrazinone-containing thrombin inhibitor 2, which is associated with irreversible incorporation of radioactivity to human microsomal tissue and in vivo in the rat. Visual inspection of the structure as well as analysis in the DEREK program does not raise any concern with regards to the presence of structural alerts. However, mechanistic studies on reactive metabolite formation depict de novo metabolic routes of bioactivation on the latent pyrazinone-ring system, leading to the formation of reactive metabolites that adduct to GSH (Figure 6.6). 

Figure 6-10 Examples of commercial blockbuster drugs, which require reactive metabolite formation for their pharmacologic action.

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