MECHANISM-BASED INACTIVATION OF HEPATIC CYTOCHROME-P450 2C6 AND P450 3A1 FOLLOWING IN-VIVO ADMINISTRATION OF YCARBONYL-1,4-DIHYDRO-2,6-DIMETHYL-4-ETHYLPYRIDINE TO RATS - DIFFERENCES FROM PREVIOUSLY OBSERVED IN-VITRO RESULTS

Using progesterone 21-hydroxylase as a selective substrate for P450 2C 6 in phenobarbital-treated male rats, and androstenedione and progeste rone 6 beta-hydroxylases as well as erythromycin N-demethylase as sele ctive markers for P450 3A1 in dexamethasone-treated female rats, we ha ve shown that these P450 isozymes undergo mechanism-based inactivation after in vivo administration of ycarbonyl-1,4-dihydro-2,6-dimethyl-4- ethylpyridine (4-ethyl DDC). These results differ from our previous st udies where no inactivation was observed after in vitro administration of 4-ethyl DDC to rat hepatic microsomes. We show that the difference s between the in vivo and in vitro effects of ethoxycarbonyl-1,4-dihyd ro-2,4,6-trimethylpyridine (DDC) analogues are due to the presence of residual 4-ethyl DDC in the in vitro experiments causing time-independ ent competitive inhibition and obscuring observation of mechanism-base d inactivation.