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THE FORMATION OF COMPLEXES ABSORBING AT 455 NM FROM CYTOCHROME P-450 AND METABOLITES OF COMPOUNDS RELATED TO SKF 525-A

MILDRED K. BUENING 1 and MICHAEL R. FRANKLIN 1

1 Department of Pharmacology, Colleges of Medicine and Pharmacy, University of Utah

A number of compounds with structural similarities to SKF 525-A (adiphenine, benactyzine, propoxyphene, diphenhydramine, desipramine, and nortriptyline) are capable of forming metabolite-cytochome P-450 complexes absorbing maximally at 455 nm when metabolized by rat hepatic microsomes. The optimum substrate concentrations for the maximum rate of formation of 455-nm complexes in microsomes from untreated rats and from rats pretreated with phenobarbital were between 25-50 µM. With microsomes from phenobarbital-induced rats, the maximum rate of formation of 455-nm complexes was proportional to the concentration of induced cytochrome P-450. The rate of formation of 455-nm complexes was highest with microsomes from phenobarbital-induced animals, intermediate with microsomes from untreated rats, and lowest with microsomes from 3-methylcholanthrene-inducd rats.

Note:
Acknowledgments. We are grateful to Smith Kline and French Laboratories for SKF 525-A·HCl, SKF acid, trimeprazine tartrate, and chlorpromazine·HCl. Ciba-Geigy Corp. donated adiphenine·HCl and imipramine·HCl. Propoxyphene·HCl, methadone·HCl and nortriptyline·HCl were supplied by Eli Lilly and Co. Sterling-Winthrop Research Laboratories provided isomethadone·HCl, and Parke, Davis and Co., diphenhydramine·HCl. Trimethobenzamide·HCl and chlorprothixene were gifts from Hoffmann-La Roche, Inc. Cyclizine·HCl was obtained from Burroughs Wellcome and Co. and desipramine·HCl from USV Pharmaceutical Corp. Merck Sharp & Dohme donated amitriptyline·HCl. Wyeth Laboratories supplied promazine·HCl and promethazine·HCl. Triflupromazine·HCl was provided by E.R. Squibb and Sons, Inc.

Submitted on February 4, 1974




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