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      Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

      Clinical Pharmacology and Therapeutics

      Area Under Curve, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, physiology, Drug Interactions, Enzyme Inhibitors, pharmacology, Half-Life, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, metabolism, pharmacokinetics, Liver, drug effects, Organic Anion Transporters

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          Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic disease. The benefits of statins are well documented. However, lipid-lowering drugs may cause myopathy, even rhabdomyolysis, the risk of which is increased by certain interactions. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4 (simvastatin acid is also metabolized by CYP2C8); their plasma concentrations and risk of myotoxicity are greatly increased by strong inhibitors of CYP3A4 (eg, itraconazole and ritonavir). Weak or moderately potent CYP3A4 inhibitors (eg, verapamil and diltiazem) can be used cautiously with small doses of CYP3A4-dependent statins. Cerivastatin is metabolized by CYP2C8 and CYP3A4, and fluvastatin is metabolized by CYP2C9. The exposure to fluvastatin is increased by less than 2-fold by inhibitors of CYP2C9. Pravastatin, rosuvastatin, and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors. Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic uptake transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins. Inhibitors of OATP1B1 may decrease the benefit/risk ratio of statins by interfering with their entry into hepatocytes, the site of action. Lipid-lowering drugs can be involved also in other interactions, including those between enzyme inducers and CYP3A4 substrate statins, as well as those between gemfibrozil and CYP2C8 substrate antidiabetics. Knowledge of the pharmacokinetic and pharmacodynamic properties of lipid-lowering drugs and their interaction mechanisms helps to avoid adverse interactions, without compromising therapeutic benefits.

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