Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin

被引:171
作者
Neuvonen, Pertti J. [1 ]
Backman, Janne T.
Niemi, Mikko
机构
[1] Univ Helsinki, Dept Clin Pharmacol, FI-00029 Helsinki, Finland
关键词
D O I
10.2165/00003088-200847070-00003
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T > C (p.Va1174A1a) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gernfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.
引用
收藏
页码:463 / 474
页数:12
相关论文
共 124 条
[1]   Simvastatin-induced rhabdomyolysis in an HIV-infected patient with coronary artery disease [J].
Aboulafia, DM ;
Johnston, R .
AIDS PATIENT CARE AND STDS, 2000, 14 (01) :13-18
[2]  
AMADOTTIR M, 1993, NEPHRON, V65, P410
[3]  
Andreou E Roseann, 2003, Can J Clin Pharmacol, V10, P172
[4]   Oral anticoagulant drug interactions with statins: Case report of fluvastatin and review of the literature [J].
Andrus, MR .
PHARMACOTHERAPY, 2004, 24 (02) :285-290
[5]  
[Anonymous], 2004, LANCET, V363, P1659
[6]  
Åsberg A, 2003, DRUGS, V63, P367
[7]   The interaction of diltiazem with lovastatin and pravastatin [J].
Azie, NE ;
Brater, DC ;
Becker, PA ;
Jones, DR ;
Hall, SD .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1998, 64 (04) :369-377
[8]   Plasma concentrations of active simvastatin acid are increased by gemfibrozil [J].
Backman, JT ;
Kyrklund, C ;
Kivistö, KT ;
Wang, JS ;
Neuvonen, PJ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2000, 68 (02) :122-129
[9]   Interactions between grapefruit juice and cardiovascular drugs [J].
Bailey D.G. ;
Dresser G.K. .
American Journal of Cardiovascular Drugs, 2004, 4 (5) :281-297
[10]   Risk for myopathy with statin therapy in high-risk patients [J].
Ballantyne, CM ;
Corsini, A ;
Davidson, MH ;
Holdaas, H ;
Jacobson, TA ;
Leitersdorf, E ;
März, W ;
Reckless, JPD ;
Stein, EA .
ARCHIVES OF INTERNAL MEDICINE, 2003, 163 (05) :553-564