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When incubated with rat hepatocytes, zomepirac yielded its S-acylglutathione thioester within minutes, but this conjugate then underwent rapid enzymatic hydrolysis.130 Rats dosed with the drug excreted zomepirac as the S-acylglutathione conjugate in their bile. All evidence pointed to the acyl-glucuronide as the reactive intermediate formed in vitro and in vivo.

Haloalkenes (86, Figure 25) are a special group of substrates of GS-transferases since they may react with GSH either by substitution to form an alkene conjugate (87) or by addition to form an alkane conjugate (88). Formation of mercapturic acids occurs as for other glutathione conjugates, but in both routes S-C cleavage of the S-cysteinyl or N-acetyl-S-cysteinyl conjugates by renal b-lyase yields thiols of significant toxicity. Indeed, these thiols rearrange by hydrohalide expulsion to form highly reactive thioketenes and/or thioacyl halides.131,132

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