ABSTRACT
I. INTRODUCTION Only a few years ago, it was generally recognized by pharmaceutical scientists that phase II metabolites of drugs, such as acyl glucuronide conjugates, are readily excreted following their formation in the body and that these metabolites are neither active nor reactive. We and others have shown that this is not generally true (1,2). Acyl glucuronide conjugates are, in fact, reactive metabolites, capable of undergoing hydrolysis, intramolecular acyl migration, and covalent binding to proteins, both in vitro and in vivo. This newly recognized reactivity has an important, but still poorly defined, bearing on biological distribution and metabolism of a widely prescribed class of drugs. It may also be directly associated
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with the perplexing toxicity of many carboxylic acid-containing drugs (3,4). It is striking that of 47 drugs withdrawn from U.S., British, and Spanish markets from 1964 through 1993 owing to severe toxicity (3,4), 10 are carboxylic acids, all of which are metabolized by humans to acyl glucuronides.
