The induction of P-450s has implications for significant cardiovascular drug interactions including statins and beta-adrenergic blocking agents.
A. Statins
The HMG-CoA reductase inhibitors, statins, are potent cholesterol-lowering agents used worldwide. Myopathy, rhabdomyolysis, and deaths have been reported in patients receiving therapy with statins. This adverse effect is caused by elevated blood levels of these agents. Patients at high risk are those concurrently taking other medications known to be metabolized by the P-450 metabolic path¬way, thereby inhibiting clearance of the statin. A main route of atorvastatin, cerivastatin, lovastatin, and simvas-tatin metabolism is via cytochrome P-450 3A4. Cases of lovastatin-induced rhabdomyolysis associated with medi¬cations such as azithromycin, erythromycin, and clarithro-mycin have been reported. Fluvastatin inhibits CYP2C9, and interactions between fluvastatin and other CYPC9
substrates such as oral anticoagulants including warfarin, oral hypoglycemic agents, phenytoin, and nonsteroidal anti-inflammatory drugs (NSAIDs) may occur.
Cerivastatin (Baycol) is metabolized by both 3A4 and 2C8; the drug was withdrawn from the market in 2001 because of the occurrence of rhabdomyolysis, kidney failure, and 52 deaths worldwide. Some of these deaths occurred because of high-dose cerivastatin therapy, and several were caused by interactions with gemfibrozil, a fibrate. A statin combined with a fibrate is not an approved combination. The fibrates are partly metabolized by the 3A4 pathway. When cerivastatin was given together with other agents such as cyclosporine, erythromycin, and itraconazole, there was a potential for drug interactions because its concentration increased by 40–300%.

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