14

PROTOCOLS FOR ASSESSMENT

OF IN VITRO AND IN VIVO

BIOACTIVATION POTENTIAL

OF DRUG CANDIDATES

ZHOUPENGZHANG ANDJINPINGGAN

Xenobiotics including drugs can be biotransformed in vivo to various
metabolites. Most of the metabolic pathways are considered as detoxification
processes, in which polar metabolites are formed and then eliminated from the
body. However, xenobiotics can also be metabolized to form reactive
intermediates that may react with macromolecules, including protein or DNA.
Thus, some reactive intermediates formed from bioactivation of xenobiotics may
be one of the causes of the observed adverse drug reactions, including drug-
induced liver toxicities (Liebler and Guengerich, 2005; Park et al., 2005; Walgren
et al., 2005). For example, Cytochrome P450-mediated bioactivation of
acetaminophen results in acute liver damage in both experimental animals and
humans (James et al., 2003). Bioactivation of some drugs can result in the
observed inhibition of P450 activity (Correia and Ortiz de Montellano, 2005).
Although formation of reactive metabolites and covalent protein binding do not
necessarily lead to toxicity, they are suspected to play a role in the idiosyncratic
reactions of drugs such as troglitazone, clozapine, and diclofenac (Park et al.,
2005). Thus, in order to minimize attrition due to bioactivation-related toxicity
and associated high development cost, a low propensity to form reactive
intermediates may be considered as a desirable property of drug candidates.

Drug Metabolism in Drug Design and Development, Edited by Donglu Zhang, Mingshe Zhu
and W. Griffith Humphreys
Copyright#2008 John Wiley & Sons, Inc.

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