PT  - JOURNAL ARTICLE
AU  - S Bezek
AU  - M Kukan
AU  - Z Kállay
AU  - T Trnovec
AU  - M Stefek
AU  - L B Piotrovskiy
TI  - Disposition of ethimizol, a xanthine-related nootropic drug, in perfused rat liver and isolated hepatocytes.
DP  - 1990 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 88--95
VI  - 18
IP  - 1
4099  - http://dmd.aspetjournals.org/content/18/1/88.short
4100  - http://dmd.aspetjournals.org/content/18/1/88.full
SO  - Drug Metab Dispos1990 Jan 01; 18
AB  - Ethimizol, 4,5-di(methylcarbamoyl)-1-ethyl-imidazole, was metabolized into at least six metabolites in an isolated perfused rat liver preparation. Based on TLC and mass spectrometry, 4-carbamoyl-5-methylcarbamoyl-1-ethyl-imidazole and 4,5-di(methylcarbamoyl)-imidazole were identified as the primary metabolites of ethimizol. These undergo further biotransformation: both can form 4(5)-carbamoyl-5(4)-methylcarbamoyl-imidazole, and, moreover, the former can be hydroxylated. Besides the identified metabolites, two polar ones of unknown structure were detected. Dose-dependent elimination of ethimizol was observed when the drug was added to the liver perfusion recirculating medium in initial reservoir concentrations of 39, 48, 85, 165, and 240 microM. The observed nonlinearity appeared to be a result of a competitive product inhibition. Similar to the parent drug, ethimizol primary metabolites were formed and eliminated in a dose-dependent manner. The uptake of ethimizol by isolated hepatocytes was extremely rapid, independent of drug concentration, over the range 0 to 250 microM, unaffected by inhibitors and independent of temperature.