RT Journal Article SR Electronic T1 The effect of enzyme induction and inhibition on the disposition of the xanthine-related nootropic drug ethimizol in perfused liver and hepatocytes of rats. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 96 OP 101 VO 18 IS 1 A1 M Kukan A1 S Bezek A1 M Stefek A1 T Trnovec A1 M Durisová A1 L B Piotrovskiy YR 1990 UL http://dmd.aspetjournals.org/content/18/1/96.abstract AB 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)