Glutathione Sconjugates

^ Conjugates (O-glucuronides, O-sulfates)

Conjugates (O-glucuronides, O-sulfates, catechol O-methyl ethers)

^ Conjugates (O-glucuronides, O-sulfates)

Macromolecular adducts Glutathione S-conjugates

Conjugates (O-glucuronides, O-sulfates)

Figure 8 Metabolic reactions centered around arene oxides. (Reproduced from Testa, B.; Mayer, J. M. Hydrolysis in Drug and Prodrug Metabolism - Chemistry, Biochemistry and Enzymology; Wiley-Verlag Helvetica Chimica Acta: Zurich, Switzerland, 2003, with the kind permission of the copyright owner, Verlag Helvetica Chimica Acta in Zurich.)

in vivo and/or in vitro. Thus, the 10,11-epoxide and the 10,11-dihydrodiol are urinary metabolites in humans and rats given the drug. In epileptic patients, the range of plasma concentrations of the epoxide and the diol was approximately 0.8-17 mM and 0.8-36 mM, respectively, i.e., a predominance of the latter.33 A number of studies have also addressed the origin of toxic reactions seen in some patients, e.g., CNS symptoms, gastrointestinal and hepatic disturbances, and hypersensitivity. Whereas no single factor seems to account for such toxic effects, the pharmacologically active 10,11-epoxide appears to contribute to clinical toxicity.34 In this perspective, the EH-catalyzed hydrolysis of the epoxide appears as a reaction of detoxification.

Interestingly, there is a marked species difference in the in vitro hydrolysis of carbamazepine 10,11-epoxide, such that the reaction was observable only in human liver microsomes but not in liver microsomal or cytosolic preparations from dogs, rabbits, hamsters, rats, or mice.35 Thus, carbamazepine appears to be a very poor substrate of epoxide hydrolases, in analogy with its simpler analogs (19, Figure 9; X = >NR, >CHR or >C=CHR). The human enzyme is exceptional in this respect.

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