RT Journal Article
SR Electronic
T1 Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1770
OP 1779
DO 10.1124/dmd.108.021725
VO 36
IS 9
A1 Hideo Takakusa
A1 Hiroshi Masumoto
A1 Hideo Yukinaga
A1 Chie Makino
A1 Shintaro Nakayama
A1 Osamu Okazaki
A1 Kenichi Sudo
YR 2008
UL http://dmd.aspetjournals.org/content/36/9/1770.abstract
AB 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 idiosyncratic drug toxicities (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 Most of the “problematic” drugs, including “withdrawn” and “warning” drugs, exhibit higher human liver microsome (HLM) in vitro covalent binding yields than the “safe” drugs. Although some of the problematic drugs that are known to undergo bioactivation other than cytochrome P450-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 postdose was found to be well correlated with the rat in vivo covalent binding to liver proteins; 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. The American Society for Pharmacology and Experimental Therapeutics