@article {Kukan96, author = {M Kukan and S Bezek and M Stefek and T Trnovec and M Durisov{\'a} and L B Piotrovskiy}, title = {The effect of enzyme induction and inhibition on the disposition of the xanthine-related nootropic drug ethimizol in perfused liver and hepatocytes of rats.}, volume = {18}, number = {1}, pages = {96--101}, year = {1990}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The once-through perfused (18 ml/min) rat liver preparations from vehicle-, phenobarbital (PB)-, and 3-methylcholanthrene (3-MC)-treated rats were used for the study of 14C-ethimizol [4,5-di(methylcarbamoyl)-1-ethyl-imidazole] elimination after input concentrations of 5, 25, 50, and 100 microM. The steady state hepatic extraction ratios decreased with increasing ethimizol inputs and were (mean +/- SD): for vehicle-treated rats, 0.361 +/- 0.038, 0.193 +/- 0.018, 0.141 +/- 0.010, and 0.100 +/- 0.011; for PB-treated rats, 0.578 +/- 0.093, 0.393 +/- 0.039, 0.302 +/- 0.028, and 0.236 +/- 0.032; and for 3-MC-treated rats, 0.913 +/- 0.057, 0.783 +/- 0.130, 0.619 +/- 0.097, and 0.447 +/- 0.053, for the respective concentrations. In recirculating experiments both PB and 3-MC increased ethimizol elimination, but the effect of the latter was considerably greater. 3-MC was also more effective than PB in enhancing the rate of formation and subsequent biotransformation of the primarily formed ethimizol metabolites, 4-carbamoyl-1-ethyl-5-methylcarbamoyl-imidazole and 4,5-di(methylcarbamoyl)-imidazole. Elimination of ethimizol was inhibited in suspension of rat hepatocytes by SKF 525-A at concentrations of 10 and 100 microM by 63\% and 60\%, respectively, and by alpha-naphthoflavone, at the same concentrations, by 71\% and 85\%, respectively. Their simultaneous addition almost completely inhibited ethimizol biotransformation. An increase of the ethimizol elimination rate in single-pass rat liver perfusion by 55\% was observed in preparations from rats treated by ethimizol in their drinking water, whereas the liver/body weight ratio, microsomal protein, and cytochrome P-450 content remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/18/1/96}, eprint = {https://dmd.aspetjournals.org/content/18/1/96.full.pdf}, journal = {Drug Metabolism and Disposition} }