ABSTRACT
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-as opposed to
ether and other glucuronides-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 associatedwith theperplexing toxicity ofmanycarboxylic acid-containingdrugs (3,4). It
is striking that out of 47 drugs withdrawn from U.S., British, and Spanish markets from 1964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.
