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Drug Metabolism and Disposition Fast Forward
First published on May 28, 2008; DOI: 10.1124/dmd.108.021725

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Received for publication April 1, 2008.
Revised May 20, 2008.
Accepted for publication May 27, 2008.

Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Hideo Takakusa 1*, Hiroshi Masumoto 1, Hideo Yukinaga 1, Chie Makino 1, Shintaro Nakayama 1, Osamu Okazaki 1, Kenichi Sudo 1

1 Daiichi sankyo Co., Ltd.

* Address correspondence to: E-mail: takakusa.hideo.yb{at}daiichisankyo.co.jp

Abstract

Bioactivation of a drug to a reactive metabolite and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including IDTs. For the interpretation of the covalent binding data in terms of risk assessment, the in vitro and in vivo covalent binding data of a variety of drugs associated with IDTs or not were determined. Most of the 'problematic' drugs, including 'withdrawn' and 'warning' drugs, exhibit higher HLM in vitro covalent binding yields than the 'safe' drugs. Although some of the 'problematic' drugs that are known to undergo bioactivation other than CYP-mediated oxidation exhibited only trace levels of HLM covalent binding like 'safe' drugs, a rat in vivo covalent binding study could assess the bioactivation of such drugs. Furthermore, the tissue distribution/retention of the drugs was also examined by rat autoradiography (ARG). The residual radioactivity in the liver observed at 72 or 168 h post-dose was found to be well correlated with the rat in vivo covalent binding to liver proteins and thus the in vivo covalent binding yields of the drugs could be extrapolated from the retention profiles observed by means of ARG. Long-term retention of radioactivity in the bone marrow was observed with some drugs associated with severe agranulocytosis, suggesting a spatial relationship between the toxicity profile and drug distribution/retention. Taken together, the covalent binding and tissue distribution/retention data of the various marketed drugs obtained in the present study should be quite informative for the interpretation of data in terms of risk assessment.


Key words: bioactivation, covalent drug binding, distribution, idiosyncratic drug reactions, reactive metabolites


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A Zone Classification System for Risk Assessment of Idiosyncratic Drug Toxicity Using Daily Dose and Covalent Binding
Drug Metab. Dispos., September 1, 2009; 37(9): 1970 - 1977.
[Abstract] [Full Text] [PDF]


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