Oxidative metabolism reactive species formation

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

The principal pathway by which unsubstituted and many substituted aromatic hydrocarbons are metabolized in mammals consists of the initial formation of arene oxides, which undergo a variety of enzymatic and nonenzymatic reactions prior to excretion of the resulting more polar, oxidized hydrocarbons via bile or urine. Taken together, these pathways represent an attempt on the part of the animal to detoxify or eliminate such nonpolar xenobiotic substances for which it has no apparent use. Although detoxification is the probable role of the arene oxide pathway, it is equally clear that chemically reactive species mediate this process. Thus, studies over the past several years have either implicated or established arene oxides in a causative role in such adverse biological reactions as cytotoxicity, mutagenesis, and carcinogenesis via covalent interaction of arene oxides with biopolymers,... 

Scheme 19) (Sun et al., 2008). The characterization of a hydroxycarboxylic acid metabolite of trovafloxacin in preclinical species (Dalvie et al., 1996) lends further support for the metabolism of the cyclopropylamine ring in trovafloxacin to a reactive intermediate. The formation of the hydroxycarboxylic acid can occur from the addition of water to the a,(3-unsaturated aldehyde via Michael addition followed by oxidation as depicted for the model compound (Scheme 19). However, the proposal for reactive metabolite formation with trovafloxacin remains a speculation since the bioactivation studies did not involve the parent fluoroquinolone and no a,(3-unsaturated aldehyde or the corresponding glutathione conjugate has been detected in trovafloxacin incubations in human liver microsomes (Sun et al., 2008). Furthermore, the primary pathways of trovafloxacin clearance in humans include phase II metabolism (iV-acetylation, acyl glucuronidation, and iV-sulfation) (Scheme 19) with very minor contributions from phase I oxidative pathways (Dalvie et al., 1997). 

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