Holtzman Carol W, Wiggins Barbara S, Spinler Sarah A
Department of Pharmacy, Christiana Care Health System, Christiana, Delaware, USA.
Pharmacotherapy. 2006 Nov;26(11):1601-7. doi: 10.1592/phco.26.11.1601.
Understanding the mechanisms of drug interactions with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has become increasingly important because of the potential for serious adverse effects, most notably myopathy. Most of the evidence supports the role of cytochrome P450 (CYP) isoenzymes in many of these drug interactions. However, P-glycoprotein (P-gp), an efflux protein located in the gastrointestinal tract, placenta, kidneys, brain, and liver, may also play a role. Results of several studies with in vitro models have shown that lovastatin, simvastatin, and atorvastatin are inhibitors for P-gp and may be substrates for this transporter as well. Pravastatin and fluvastatin consistently demonstrate no significant inhibition of P-gp. Drug interaction studies involving statins and digoxin support a role for P-gp. Many additional drugs such as diltiazem, verapamil, itraconazole, ketoconazole, and cyclosporine, as well as dietary supplements such as St. John's wort and grapefruit juice, interact with statins and are modulators of both CYP3A4 and P-gp. However, the role of P-gp in these specific drug interactions remains unclear.
由于存在严重不良反应的可能性，尤其是肌病，了解药物与3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）的相互作用机制变得越来越重要。大多数证据支持细胞色素P450（CYP）同工酶在许多此类药物相互作用中发挥的作用。然而，位于胃肠道、胎盘、肾脏、大脑和肝脏的外排蛋白P-糖蛋白（P-gp）也可能起作用。几项体外模型研究结果表明，洛伐他汀、辛伐他汀和阿托伐他汀是P-gp的抑制剂，也可能是该转运蛋白的底物。普伐他汀和氟伐他汀始终未显示出对P-gp有显著抑制作用。涉及他汀类药物和地高辛的药物相互作用研究支持P-gp发挥作用。许多其他药物，如地尔硫卓、维拉帕米、伊曲康唑、酮康唑和环孢素，以及膳食补充剂，如圣约翰草和葡萄柚汁，都与他汀类药物相互作用，并且是CYP3A4和P-gp的调节剂。然而，P-gp在这些特定药物相互作用中的作用仍不清楚。
