Statin pharmacokinetics
Authors:
J. A. Hubáček 1,2; V. Adámková 1; K. Zídková 3; R. Češka 3; L. Zlatohlávek 3; T. Štulc 3; A. Hořínek 3; M. Vráblík 3
Authors‘ workplace:
Institut klinické a experimentální medicíny Praha, ředitel doc. MUDr. Jan Malý, CSc.
1; Centrum výzkumu chorob srdce a cév IKKEM Praha, ředitel prof. MUDr. Bohuslav Ošťádal, DrSc.
2; III. interní klinika 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Štěpán Svačina, DrSc., MBA
3
Published in:
Vnitř Lék 2008; 54(1): 62-67
Category:
Review
Overview
Reducing high levels of plasmatic lipoids (LDL-cholesterol and triglycerides) is one of the most important steps in the prevention and treatment of cardiovascular diseases. In the majority of cases, treatment based on lifestyle changes (changes in dietary habits, more physical activity) is not sufficient and pharmacotherapy becomes necessary. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are a well tolerated first-choice drug in patients with dyslipidemia. However, great variability of statin effects has been observed in different patients on the same therapy, and the cause clearly resides in different genetic characteristics of each individual, influencing the effect of therapy. The influence of different genetic variants has been described, but the control of response to hypolipidemic therapy is most likely subject to polygenic control. The analysis of multiple gene combinations may help detect the "hyper-" and "hypo-" responders, i.e. individuals with a good response to treatment (allowing for starting with a lower dose of the drug), and those with an insufficient response to treatment (in whom statin shall not be the drug of first choice), or it may help detect the patients who are more likely to develop severe adverse events. Studies with different designs describe that for instance genes (and their variants) for cytochromes, apolipoprotein E and A1 and cholesterol 7α-hydroxylase may be important genetic determinants of the effect of pharmacological treatment of dyslipidemia and play a role in the individualisation of treatment.
Keywords:
statins – dyslipidemia – gene variability – pharmacogenetics
Sources
1. Poledne R, Škodová Z. Changes in nutrition, cholesterol concentration, and cardiovascular disease mortality in the Czech population in the past decade. Nutrition 2000; 16: 785-786.
2. Cífková R. Prevence ischemické choroby srdeční v dospělém věku. Kapitoly z kardiologie 2002; 2: 122-139.
3. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149-1158.
4. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623-1630.
5. Adámková V. Farmakologická léčba hyperlipoproteinemií. Practicus 2004; 3: 189-192.
6. Adámková V. Nejnovější trendy léčby závažné dyslipidemie v praxi. Practicus 2007; 6: 12-14.
7. Shovman O, Levy Y, Gilburd B et al. Antiinflammatory and immunomodulatory properties of statins. Immunol Res 2002; 25: 271-285.
8. Browning DR, Martin RM. Statins and risk of cancer: A systematic review and metaanalysis. Int J Cancer 2007; 120: 833-843.
9. Švejda P. Statiny a osteoporóza. Vnitř Lék 2006; 52: 1190-1193.
10. Vrablík M, Češka R. Statiny: od lipidologii ke kardiologii. Klinická farmakologie 2005; 8: 47-49.
11. Vrablík M. Statiny. Practicus 2006; 6: 219-222.
12. Siest G, Ferrari L, Accaoui MJ et al. Pharmacogenomics of drugs affecting the cardiovascular system. Clin Chem Lab Med 2003; 41: 590-599.
13. Siest G, Jeannesson E, Berrahmoune H et al. Pharmacogenomics and drug response in cardiovascular disorders. Pharmacogenomics 2004; 5: 779-802.
14. Takane H, Miyata M, Burioka N et al. Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy. J Hum Genet 2006; 51: 822-826.
15. Talmud PJ Gene-environment interaction and its impact on coronary heart disease risk. Nutr Metab Cardiovasc Dis 2007; 17: 148-152.
16. Schmitz G, Langmann T. Pharmacogenomics of cholesterol-lowering therapy. Vascul Pharmacol 2006; 44: 75-89.
17. Kajinami K, Brousseau ME, Ordovas JM et al. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol 2004; 93: 104-107.
18. Fischer V, Johanson L, Heitz F et al. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999; 27: 410-416.
19. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16.
20. Fiegenbaum M, da Silveira FR, Van derSand CR et al. The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment. Clin Pharmacol Ther 2005; 78: 551-558.
21. Chasman DI, Posada D, Subrahmanzan L et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291: 2821-2827.
22. Heath KE, Gudnason V, Humphries SE et al. The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. Atherosclerosis 1999; 143: 41-54.
23. Miltiadous G, Xenophontos S, Bairaktari E et al. Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. Pharmacogenet Genomics 2005; 15: 219-225.
24. Ye P, Shang Y, Ding X. The influence of apolipoprotein B and E gene polymorphisms on the response to simvastatin therapy in patients with hyperlipidemia. Chin Med Sci J 2003; 18: 9-13.
25. Hubacek JA, Pitha J, Skodova Z et al. Polymorphisms in CYP-7A1, nor APOE, influence the change in plasma lipids in response to population dietary change in an 8-year follow-up; results from the Czech MONICA study. Clin Biochem 2003; 36: 263-267.
26. Hubacek JA, Bobkova D Role of cholesterol 7 alpha-hydroxylase (CYP7A1) in nutrigenetics and pharmacogenetics of cholesterol lowering. Mol Diagn Ther 2006; 10: 93-100.
27. Kajinami K, Brousseau ME, Ordovas JM et al. Interaction between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol lowering response to atorvastatin. Atherosclerosis 2004; 175: 287-293.
28. Kajinami K, Brousseau ME, Ordovas JM et al. A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis 2005; 180: 407-415.
29. Hubacek JA, Poledne R. Apolipoprotein E a jeho role v lipidovém metabolismu, kardiovaskulárních onemocněních a Alzheimerově chorobě. Prakt Lék 1998; 78: 162-165.
30. Ordovas JM, Mooser V. The APOE locus and the pharmacogenetics of lipid response. Curr Opin Lipidol 2002; 13: 113-117.
31. Kajinami K, Takehoshi N, Brousseau ME et al. Pharmacognetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 2004; 177: 219-234.
32. Garcia-Garcia AB, Gonzalez C, Real JT et al. Influence of microsomal triglyceride transfer protein promoter polymorphism -493 GT on fasting plasma triglyceride values and interaction with treatment response to atorvastatin in subjects with heterozygous familial hypercholesterolaemia. Pharmacogenet Genomics 2005; 15: 211-218.
33. Lahoz C, Pena R, Mostaza JM et al. Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy. Atherosclerosis 2003; 168: 289-295.
34. Hubacek JA, Waterworth DM, Pitha J et al. Polymorphisms in the lipoprotein lipase and hepatic lipase genes and plasma lipid values in the Czech population. Physiol Res 2001; 50: 345-351.
35. Jansen H, Verhoeven AJ, Weeks L et al. Common C-to-T substitution at position -480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients. Arterioscler Thromb Vasc Biol 1997; 17: 2837-2842.
36. Murtomaki S, Tahvanainen E, Antikainen M et al. Hepatic lipase gene polymorphisms influence plasma HDL levels. Results from Finnish EARS participants. European Atherosclerosis Research Study. Arterioscler Thromb Vasc Biol 1997; 17: 1879-1884.
37. Lahoz C, Pena R, Mostaza JM et al. The -514C/T polymorphism of the hepatic lipase gene significantly modulates the HDL-cholesterol response to statin treatment. Atherosclerosis 2005; 182: 129-134.
38. Harada LM, Carrilho AJ, Oliveira HC et al. Regulation of hepatic cholesterol metabolism in CETP/LDLr mice by cholesterol feeding and by drugs (cholestyramine and lovastatin) that lower plasma cholesterol. Clin Exp Pharmacol Physiol 2006; 33: 1209-1215.
39. Salek L, Lutucuta S, Ballantyne CM et al. Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin. J Mol Med 2002; 80: 737-744.
40. Fiegenbaum M, Silveira FR, Van der Sand CR et al. Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes. Pharmacogenomics J 2005; 5: 359-364.
41. Kashani A, Phillips CO, Foody JM et al. Risks associated with statin therapy. Circulation 2006; 114: 2788-2797.
42. Weggemans RM, Zock PL, Urgent R et al. Differences between men and women in the response of serum cholesterol to dietary changes. Eur J Clin Invest 1999; 29: 827-834.
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