In vitro evaluation of the potential for drug-induced toxicity based on (35)S-labeled glutathione adduct formation and daily dose.
BACKGROUND
Drug-induced toxicity such as idiosyncratic drug toxicity is believed to be reduced when either reactive metabolite formation or exposure to a drug is minimized. The objective of the present study was therefore to clarify the relationship between the daily doses, the formation rates of reactive metabolite adduct with (35)S-glutathione (RM-GS) and the safety profiles of compounds.


RESULTS
The RM-GS formation rates for 113 test compounds were determined by incubation with human liver microsomes, and the test compounds were classified into three categories of safe, warning and withdrawn/black box warning. A total of 23 out of 28 withdrawn/black box warning drugs showed both a RM-GS formation rate of over 1 pmol/30 min/mg protein and a dose of over 100 mg.


CONCLUSIONS
These results suggest that when compounds are plotted in this region, the compounds would have a relatively high idiosyncratic drug toxicity potential.
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710, Japan. miyaji.yoshihiro.gw@rdn.daiichisankyo.co.jp
Yoshihiro
Y
Miyaji
Chie
C
Makino
Atsushi
A
Kurihara
Wataru
W
Suzuki
Osamu
O
Okazaki
D004008:Diclofenac / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013462:Sulfur Radioisotopes / Q000737:chemistry; D013988:Ticlopidine / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D004364:Pharmaceutical Preparations; D013462:Sulfur Radioisotopes; D004008:Diclofenac; D005978:Glutathione; D013988:Ticlopidine