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Molecular Pharmacology, Vol 6, 206-212, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Two-Substrate Kinetics of Drug-Metabolizing Enzyme Systems of Hepatic Microsomes

ALVITO P. ALVARES 1 and G. J. MANNERING 1

1 Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

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.

Note:
ACKNOWLEDGMENT The authors gratefully acknowledge the able technical assistance of Mrs. Jannice Shoeman.

Submitted on January 3, 1970




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