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Molecular Pharmacology, Vol 2, 319-327, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Drug Metabolism

I. Kinetics of the Inhibition of the N-Demethylation of Ethylmorphine by 2-Diethylaminoethyl 2,2-Diphenylvalerate HCI (SKF 525-A) and Related Compounds

M. W. ANDERS 1 and G. J. MANNERING 1

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

SKF 525-A and ten congeners were incubated with hepatic microsomes, and all were found to be N-dealkylated. The kinetics of the inhibition of the N-demethylation of ethylmorphine by the eleven compounds was studied and found to be competitive in all cases. These results strongly suggest that SKF 525-A type compounds produce their effects by combining with the active site of time N-demethylase, not by altering the permeability of the lipoid membrane of the microsomime or by uncoupling an oxidative mechanism as has been postulated by others. Kinetic data were presented which indicated that many of these compounds produce their inhibitory effects by serving as alternative substrates. Kinetic evidence is also presented to support the view that the activity of SKF 525-A may be due in part to one or more of its metabolites.

Note:
ACKNOWLEDGMENTS This research was supported by USPHS grant No. GM-12543. Part of this material appears in abstract form in Federation Proc. 23, 537 (1964) and in a thesis by M. W. Anders in partial fulfillment of the requirements for the Ph.D. degree in the Department of Pharmacology, University of Minnesota, 1964. The authors gratefully acknowledge the able technical assistance of Mrs. Sheila Ham and Mrs. Margaret (Chang) Lu.

Submitted on February 17, 1966




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