Drug Metabolism in Drug Design and Development Basic Concepts and Practice

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metabolite-mediated toxicity pathway is indeed thought to be animal specific
then it is necessary to demonstrate this specificity in animals and humans or
show that there is enough of a safety margin established in animals such that
there is minimal concern in humans. There are numerous examples in the
literature where bioactivation of a xenobiotic to a reactive intermediates is
proposed to lead to toxicity (Baillie and Kassahun, 2001; Evans et al., 2004).
However, there are very few examples for marketed drugs where detailed
studies have been conducted to explain toxicity findings in animals that are not
relevant to humans due to lack of that pathway in humans. The example of rat-
specific toxicity of efavirenz is discussed below. Similarly, investigative
approaches can be used when unexpected drug–drug interactions or toxicities
occur in humans. There are two examples provided below were inhibition of a
drug-metabolizing enzyme could play a possible role in the observed drug–drug
interaction or toxicity in humans.


9.6.1 Rat-Specific Toxicity of Efavirenz Caused
by Species-Specific Bioactivation


Efavirenz (Sustiva), an anti-HIV drug was found to cause necrosis of the renal
proximal tubular epithelium in rats after an oral dose of 700 mg/kg. Similar
toxicity was not observed in cynomolgus monkey or human. The nephrotoxi-
city in rats was attributed to the formation of a glutathione adduct that was
further processed to a mixture of cysteine–glycine adducts and cysteine adducts
(Mutlib et al., 1999). Mechanistic studies with stable-labeled efavirenz and
coadministration with acivicin, a g-glutamyltranspeptidase inhibitor, con-
firmed that the formation of the glutathione conjugate and its processing
finally to the cysteine conjugate was necessary for eliciting the nephrotoxicity in
rats (Mutlib et al., 2000). This glutathione conjugation pathway was not
observed in cynomolgus monkey or in humans. This demonstration of species-
specific pathway and its absence in humans, followed by detailed mechanistic
studies, helped to place this issue in the proper perspective in terms of risk to
patients. It was concluded that the nephrotoxicity in rat observed at high doses
was not a safety concern in humans.


9.6.2 UGT1A1 Inhibition-Mediated Hyperbilirubinemia
by HIV Protease Inhibitors


In this example, investigative studies were conducted to address an issue of
unconjugated hyperbilirubinemia in human subjects observed after adminis-
tration of HIV protease inhibitors indinavir and atazanavir. The proposed
hypothesis for hyperbilirubinemia was inhibition of glucuronidation of
bilirubin by these two drugs, a key step in the excretion of bilirubin into
bile. To test this hypothesis, a panel of HIV protease inhibitors, including
atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, were


EXAMPLES OF ROLE OF DRUG METABOLISM 279

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