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Molecular Pharmacology, Vol 2, 328-334, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Drug Metabolism

II. Metabolism of 2-Diethylaminoethyl 2,2-Diphenylvalerate HCI (SKF 525-A)

M. W. ANDERS 1, A. P. ALVARES 1, and G. J. MANNERING 1

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

The metabolism of SKF 525-A by washed hepatic microsomes from the rat was studied. The secondary amine derivative, 2-ethylaminoethyl 2,2-diphenylvalerate HCl (SKF 8742-A) was identified as a metabolite. A second metabolite, designated metabolite I, was also observed. The acidic hydrolysis product of SKF 525-A, 2,2-diphenylvalerate (SKF 2314), was identified and the rate of hydrolysis of SKF 525-A by washed microsomes was measured. Metabolite I was not found in microsomal preparations that had been incubated with SKF 8742-A. No SKF 525-A or SKF 8742-A was recovered from the urine, bile, or feces of rats that had received these compounds, nor were metabolites found in these materials. The primary amine analog of SKF 525-A, 2-aminoethyl 2,2-diphenylvalerate hydrobromide (AEDV) was synthesized. AEDV was shown to be a competitive inhibitor of the N-demethylation of ethylmorphine with an inhibition constant quite similar to those of SKF 525-A and SKF 8742-A.

Note:
ACKNOWLEDGMENTS This research was supported by USPHS grant No. GM-12543. Part of this material appears in a thesis by M. W. Anders in partial fulfillment of time requirements for the Ph.D. degree in the Department of Pharmacology, University of Minnesota, 1964. The authors gratefully acknowledge the able technical assistance of Mr. Donald W. Shoeman and Mrs. Sheila Ham. We are grateful to Dr. Philip S. Portoghese for his helpful suggestions regarding the synthesis of AEDV.

Submitted on February 17, 1966




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2-Diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) Revisited: Comparative Cytochrome P450 Inhibition in Human Liver Microsomes by SKF525A, Its Metabolites, and SKF-Acid and SKF-Alcohol
Drug Metab. Dispos., December 1, 2008; 36(12): 2539 - 2546.
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