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Enantioselective N-oxygenation of verapamil by the hepatic flavin- containing monooxygenase

JR Cashman

Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.

The chemical and enzymatic N-oxygenation of verapamil was investigated. Verapamil N-oxide is readily synthesized by chemical means. It is not indefinitely stable, however, and undergoes Cope-type elimination to produce 3,4-dimethoxystyrene and a hydroxylamine. The major stable metabolite observed during the metabolism of verapamil with rat and hog liver microsomes and purified flavin-containing monooxygenase is 3,4- dimethoxystyrene. 3,4-Dimethoxystyrene is formed at a rate 4 times that of nor-verapamil. Studies suggest that N-oxygenation is catalyzed largely by the flavin-containing monooxygenase and N-demethylation is catalyzed by cytochrome P-450. This conclusion is based on the effects of cytochrome P-450 inhibitors and positive effectors for the flavin- containing monooxygenase as well as on studies with the purified enzyme. In the presence of rat and hog liver microsomes, significant stereoselectivity in N-oxygenation of verapamil is observed (S/R ratio of 3.1 and 4.1, respectively). With purified hog and rat hepatic flavin- containing monooxygenase, the stereoselectivity for verapamil N- oxygenation (S/R ratio of 10.1 and 6.6, respectively) suggests a role for this enzyme in the stereoselective first-pass metabolism of verapamil.

Volume 36, Issue 3, pp. 497-503, 09/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1989 by the American Society for Pharmacology and Experimental Therapeutics