Effects of FK037 on the Aldehyde Dehydrogenase and the Drug Metabolizing Enzyme System in Rats

• Published in: Drug Metabolism and Pharmacokinetics Vol. 10; no. 3; pp. 359 - 368
• Main Authors: HIRAIWA, Tomoko, UEDA, Yoshiko, TOKUMA, Yoji, TAKESHITA, Kohji, TERASHITA, Shigeyuki, NIWA, Toshiro, TOZUKA, Zenzaburo, NARITOMI, Youichi, SAITO, Naomi, HATA, Takehisa
• Format: Journal Article
• Language: English
• Published: The Japanese Society for the Study of Xenobiotics 1995
• Subjects: Acetaldehyde; Aldehyde dehydrogenase; Disulfiram-like reaction; Drug metabolizing enzyme; Ethanol metabolism; FK037; Rat
• ISSN: 0916-1139
• DOI: 10.2133/dmpk.10.359

The effects of FK037 on the aldehyde dehydrogenase and the drug metabolizing enzyme system in male rat liver were studied. 1. When male rats were given ethanol intraperitoneally at 24 hours after a single administration of FK037 (100 or 1000 mg/kg), the blood acetaldehyde concentration was not affected by the administration of FK037. On the other hand, a marked increase of blood acetaldehyde level was observed after by administration of cefoperazone (1000 mg/kg) and disulfiram (500 mg/kg), which were reported to have disulfiram-like reaction. In addition, the administration of cefoperazone and disulfiram caused a depression of hepatic mitochondrial lowKm aldehyde dehydrogenase (ALDH) activity. However, mitochondrial low-Km ALDH activity was not changed by the administration of FK037. Further, disulfiram, cefoperazone and 1-methyl-tetrazol-5-thiol (MTT) which is derived from 3-substituent of cefoperazone caused a inhibition of low Km-ALDH activity, while FK037 and 5-amino-1'-(2-hydroxyethyl)-pyrazole (AHP) which is derived from 3-substituent of FK037 did not inhibit this enzyme activity in vitro. From these results, we conclude that FK037 does not affect the aldehyde dehydrogenase in male rats. 2. There were no significant effects on cytochrome P-450 and b5 contents, NADPH-cytochrome c reductase, aminopyrine demethylase, aniline hydroxylase and ethoxyresorufin deethylase on three days after intravenous administration of FK037 with 20 and 100 mg/kg/day to male rats. These results suggest that FK037 does not affect the hepatic drug metabolizing enzyme system in male rats.