The effect of enzyme induction and inhibition on the disposition of the xanthine-related nootropic drug ethimizol in perfused liver and hepatocytes of rats.
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)
Kukan
M
M
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Czechoslovakia.
Bezek
S
S
Stefek
M
M
Trnovec
T
T
Durisová
M
M
Piotrovskiy
L B
LB
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005042:Etimizol / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011619:Psychotropic Drugs / Q000493:pharmacokinetics*; D051381:Rats
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011506:Proteins; D011619:Psychotropic Drugs; D008748:Methylcholanthrene; D009320:Atrial Natriuretic Factor; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D005042:Etimizol; D010634:Phenobarbital