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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Drug Metabolism

IV. Induction of Drug Metabolism by 2-Diethylaminoethyl 2,2-Diphenylvalerate HCl(SKF 525-A) and 2,4-Dichloro-6-phenylphenoxyethyldiethylamine HBr (Lilly 18947) and the Effect of Induction on the Inhibitory Properties of SKF 525-A Type Compounds

M. W. ANDERS and G. J. MANNERING
Molecular Pharmacology July 1966, 2 (4) 341-346;
M. W. ANDERS
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455
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G. J. MANNERING
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455
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Abstract

The chronic administration (5 days) of SKF 525-A and Lilly 18947 to rats induced increased microsomal enzyme activity as measured by the N-dealkylation of these compounds themselves as well as that of ethylmorphine. In rats whose rates of hexobarbital metabolism had been increased as a result of the repeated administration of SKF 525-A, hexobarbital metabolism was still inhibited when a final dose of SKF 525-A was given. Similarly, in phenobarbital treated rats, SKF 525-A, its product of N-dealkylation, 2-ethylaminoethyl 2,2-diphenylvalerate HCl (SKF 8742-A), and its primary amine analog, 2-aminoethyl 2,2-diphenylvalerate HBr (AEDV), were all effective inhibitors of the enhanced rate of hexobarbital metabolism. These results are explained on the basis that the inductive process involves the synthesis of new enzymic protein that is as readily inhibited by SKF 525-A type compounds as that which was present before induction. Even though the rate of metabolism of SKF 525-A is increased as a result of induction it continues to exert its effects through its products of N-dealkylation, which are also excellent inhibitors.

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.

  • Copyright ©, 1966, by Academic Press Inc.

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Molecular Pharmacology
Vol. 2, Issue 4
1 Jul 1966
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Research ArticleArticle

Inhibition of Drug Metabolism

M. W. ANDERS and G. J. MANNERING
Molecular Pharmacology July 1, 1966, 2 (4) 341-346;

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Research ArticleArticle

Inhibition of Drug Metabolism

M. W. ANDERS and G. J. MANNERING
Molecular Pharmacology July 1, 1966, 2 (4) 341-346;
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