Two-substrate kinetics of drug-metabolizing enzyme systems of hepatic microsomes.

TLDR: Two-substrate kinetics was employed to show that more than one microsomal system functions in the dealkylation of drugs, and different enzyme systems or rate-limiting components appear to be involved in the N -demethylation of morphine and the O -dem methylation of norcodeine.

Abstract: Two-substrate kinetics was employed to show that more than one microsomal system functions in the dealkylation of drugs. Evidence is also presented to show that in some dealkylation reactions a common enzyme system on rate-limiting component is involved. Employing microsomes from the male rat, it was concluded that the same enzyme system or rate-limiting component is involved in the N -demethylation of the l- and d -forms of 3-methoxy- N -methylmorphinan and in the N -deethylation of the tertiary amine, 2-diethylaminoethyl 2,2-diphenylvalerate·HCl (SKF 525-A), and its analogue, the secondary amine, 2-ethylaminoethyl 2,2-diphenylvalerate·HBr (SKF 8742-A). Using microsomes from untreated rats or from rats treated with phenobarbital or 3-methylcholanthrene, it was shown that the same enzyme system N -demethylates ethylmorphine and N -methylaniline. Different enzyme systems or rate-limiting components appear to be involved in the N -demethylation of morphine and the O -demethylation of norcodeine. Using microsomes from untreated rats, different N -demethylase systems metabolized ethylmorphine and morphine, but microsomes from phenobarbital-treated rats employed the same system. ACKNOWLEDGMENT The authors gratefully acknowledge the able technical assistance of Mrs. Jannice Shoeman.