INFLUENCE OF SOME NOVEL N-SUBSTITUTED AZOLES AND PYRIDINES ON RAT HEPATIC CYP3A ACTIVITY

A series of N-substituted heteroaromatic compounds structurally relate d to clotrimazole was synthesized, and the effects of these compounds on ethosuximide clearance in rats were determined as a measure of thei r abilities to induce cytochrome P4503A (CYP3A) activity. Ethosuximide clearance and in, vitro erythromycin N-demethylase activity were show n to correlate. In this series, imidazole or other related heteroaroma tic ''head groups'' were linked to triphenylmethane or other phenylmet hane derivatives. Within the series, it was found that 1-triphenylmeth ane-substituted imidazoles elicited the greatest increase in CYP3A act ivity, and that among the triphenylmethyl-substituted imidazoles, the highest activities were achieved by the substitution of F-or Cl- in ei ther the meta or para position of one of the phenyl rings. Diphenylmet hyl-substituted pyridine was effectively devoid of activity. Compounds eliciting the largest increase in CYP3A activity (viz. 1-[(3-fluoroph enyl)diphenylmethyl]imidazole, 1-[(4-fluorophenyl) diphenylmethyl] imi dazole, and 1-[tri-(4-fluorophenyl)methyl]imidazole) produced little o r no increase in ethoxyresorufin O-dealkylase (EROD) activity (i.e. CY P1A), whereas benzylimidazole, which elicited only a small increase in CYP3A activity, produced an almost 9-fold increase in CYP1A activity. For a series of eleven compounds exhibiting a wide range of influence on CYP3A activity, a positive correlation was found between ethosuxim ide clearance and hepatic CYP3A mRNA levels. (C) 1998 Elsevier Science Inc.