Cashman J R
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
Mol Pharmacol. 1989 Sep;36(3):497-503.
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.
研究了维拉帕米的化学和酶促N-氧化反应。维拉帕米N-氧化物可通过化学方法轻松合成。然而，它并非无限稳定，会发生科普型消除反应生成3,4-二甲氧基苯乙烯和一种羟胺。在维拉帕米与大鼠和猪肝微粒体以及纯化的含黄素单加氧酶代谢过程中观察到的主要稳定代谢产物是3,4-二甲氧基苯乙烯。3,4-二甲氧基苯乙烯的生成速率是去甲维拉帕米的4倍。研究表明，N-氧化反应主要由含黄素单加氧酶催化，N-去甲基化反应由细胞色素P-450催化。这一结论基于细胞色素P-450抑制剂和含黄素单加氧酶的正效应剂的作用以及对纯化酶的研究。在大鼠和猪肝微粒体存在的情况下，观察到维拉帕米N-氧化反应具有显著的立体选择性（S/R比分别为3.1和4.1）。对于纯化的猪和大鼠肝脏含黄素单加氧酶，维拉帕米N-氧化反应的立体选择性（S/R比分别为10.1和6.6）表明该酶在维拉帕米的立体选择性首过代谢中起作用。
