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01-04-2001 | Review Articles

Clinical Pharmacokinetics of Fluvastatin

Authors: Charity D. Scripture, Professor John A. Pieper

Published in: Clinical Pharmacokinetics | Issue 4/2001

Abstract

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models.

Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin.

CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance.

In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.

Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years follow-up from the Framingham study. JAMA 1987; 257: 2176–80PubMedCrossRef

Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269: 3015-23

Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9

Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9PubMedCrossRef

Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997; 336(3): 153–62CrossRef

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333(20): 1301–7PubMedCrossRef

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279(20): 1615–22PubMedCrossRef

Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339(19): 1349–57CrossRef

Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986; 232: 34–47PubMedCrossRef

10.

Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425–30PubMedCrossRef

11.

Desager JP, Horsmans Y. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet 1996; 31: 348–71PubMedCrossRef

12.

Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors: similarities and differences. Clin Pharmacokinet 1997; 32: 403–25PubMedCrossRef

13.

Hayashi K, Kurokawa J, Nomura S, et al. Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells. Biochim Biophys Acta 1993; 1167: 223–5PubMedCrossRef

14.

Rosenson RS, Tangney C. Anti-atherothrombotic properties of statins. JAMA 1998; 279: 1643–50PubMedCrossRef

15.

Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999; 84: 413–28PubMedCrossRef

16.

Bellosta S, Bernini F, Ferri N, et al. Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis 1998; 137 Suppl.:S101–9PubMedCrossRef

17.

Bernini F, Scurati N, Bonfadini G, et al. HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol 1995; 15: 1352–8PubMedCrossRef

18.

Soma MR, Donetti E, Parolini C, et al. HMG-CoA reductase inhibitors: in vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb 1993; 13: 571–8PubMedCrossRef

19.

Bandoh T, Mitani H, Niihasi M, et al. Fluvastatin suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition. J Cardiovasc Pharmacol 2000; 35: 136–44PubMedCrossRef

20.

Mitani H, Bandoh T, Ishikawa J, et al. Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. Br J Pharmacol 1996; 119: 1269–75PubMedCrossRef

21.

Plosker Gl, Wagstaff AJ. Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia. Drugs 1996;51:433–59PubMedCrossRef

22.

Illingworth DR, Tobert JA. Areview of clinical trials comparing HMG-CoA reductase inhibitors. Clin Ther 1994; 16: 366–85PubMed

23.

Langtry HD, Markham A. Fluvastatin: a review of its use in lipid disorders. Drugs 1999; 57: 583–606PubMedCrossRef

24.

Yuan JN, Tsai MY, Hegland J, et al. Effects of fluvastatin (XU62-320), an HMG-CoA reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis 1991; 87: 147–57PubMedCrossRef

25.

Serruys PW, Foley DP, Jackson G, et al. A randomized placebocontrolled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty: final results of the fluvastatin angiographic restenosis (FLARE) trial. Eur Heart J 1998; 20: 58–69CrossRef

26.

Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (lipoprotein and coronary atherosclerosis study [LCAS]). Am J Cardiol 1997; 80: 278–86PubMedCrossRef

27.

Riegger G, Abletshauser C, Ludwig M, et al. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 1999; 144: 263–70PubMedCrossRef

28.

Kathawala FG. HMG-CoA reductase inhibitors: an exciting development in the treatment of hyperlipoproteinemia. Med Res Rev 1991; 11: 121–46PubMed

29.

Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 1992; 32: 630–8PubMed

30.

Lindahl A, Sandstrom R, Ungell AL, et al. Jejunal permeability and hepatic extraction of fluvastatin in humans. Clin Pharmacol Ther 1996; 60: 493–503PubMedCrossRef

31.

Smith HT, Jokubaitis LA, Troendle AJ, et al. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens 1993; 6 Suppl. (II Pt 2): 375S–382SPubMed

32.

Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53PubMedCrossRef

33.

Appel S, Dingemanse J. Clinical pharmacokinetics of fluvastatin with reference to other HMG-CoA reductase inhibitors. Drugs Today 1996; 32 Suppl. A: 37–55

34.

Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (±)-fluvastatin. Clin Pharmacol Ther 1995; 58: 412–7PubMedCrossRef

35.

De Waziers I, Cugnenc PH, Yang CS, et al. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253: 387–94PubMed

36.

Tse FLS, Smith HT, Ballard FH, et al. Disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in mouse, rat, dog, and monkey. Biopharm Drug Dispos 1990; 11: 519–31PubMedCrossRef

37.

Tse FL, Nickerson DF, Yardley WS. Binding of fluvastatin to blood cells and plasma proteins. J Pharm Sci 1993; 82: 942–7PubMedCrossRef

38.

Guillot F, Misslin P, Lemaire M. Comparison of fluvastatin and lovastatin blood-brain barrier transfer using in vitro and in vivo methods. J Cardiovasc Pharmacol 1993; 21: 339–46PubMedCrossRef

39.

Tse FLS, Labbadia D. Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase in the rabbit. Biopharm Drug Dispos 1992; 13: 285–94PubMedCrossRef

40.

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: 410–6PubMed

41.

Transon C, Leeman T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolizing cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15PubMedCrossRef

42.

Dain JG, Fu E, Gorski J, et al. Biotransformation of fluvastatin sodium in humans. Drug Metab Dispos 1993; 21: 567–72PubMed

43.

Pieper JA, Johnson KE. Lidocaine. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics, 1992: 21.1–21.37

44.

Deslypere JP. Clinical implications of the biopharmaceutical properties of fluvastatin. Am J Cardiol 1994; 73: 12D–17DPubMedCrossRef

45.

Lintott CJ, Scott RS, Bremer JM, et al. Fluvatatin for dyslipoproteinemia with or without concomitant chronic renal insufficiency. Am J Cardiol 1995; 76(2): 97A–101APubMedCrossRef

46.

Dujovne CA, Davidson MH. Fluvastatin administration at bedtime versus with the evening meal: a multicenter comparison of bioavailability, safety, and efficacy. Am J Med 1994; 96 Suppl. 6A: 37S–40SPubMedCrossRef

47.

Smit JW, Wijnne HJ, Schobben F, et al. Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin. Am J Cardiol 1995; 76(2): 89A–96APubMedCrossRef

48.

Leitersdorf E, Eisenberg S, Eliav O, et al. Efficacy and safety of high dose fluvastatin in patients with familial hypercholesterolemia. Eur J Clin Pharmacol 1993; 45: 513–8PubMedCrossRef

49.

Sprecher DL, Abrams J, Allen JW, et al. Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients. Ann Intern Med 1994; 120: 537–43PubMed

50.

Jokubaitis L. Fluvastatin in combination with other lipid-lowering agents. Br J Clin Pract 1996; 77 Suppl. A: 28–32

51.

Hagen E, Istad H, Bodd E, et al. Fluvastatin efficacy and tolerability in comparison and in combination with cholestyramine. Eur J Clin Pharmacol 1994; 46: 445–9PubMedCrossRef

52.

Blum CB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol 1994; 73: 3D–11DPubMedCrossRef

53.

Garnett WR. The pharmacology of fluvastatin, a new HMG-CoA reductase inhibitor. Clin Cardiol 1994; 17 Suppl. IV: 3–10

54.

Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health-Syst Pharm 1995; 52: 1639–45PubMed

55.

Aberg J, Eriksson U, Fager G. Effects of erythromycin on plasma fluvastatin levels: a pharmacokinetic study [abstract]. Atherosclerosis 1997; 134: 118ACrossRef

56.

Meadowcroft AM, Williamson KM, Patterson JH, et al. The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39: 418–24PubMedCrossRef

57.

Appel S, Rufenacht T, Kalafsky G, et al. Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin dependent diabetes mellitus. Am J Cardiol 1995; 76(2): 29A–32APubMedCrossRef

58.

Li PK, Mak TW, Wang AY, et al. The interaction of fluvastatin and cyclosporine A in renal transplant patients. Int J Clin Pharmacol Ther 1995; 33: 246–8PubMed

59.

Holdaas H, Hartmann A, Strenstrom J, et al. Effect of fluvastatin for safely lowering atherogenic lipids in renal transplant patients receiving cyclosporine. Am J Cardiol 1995; 76: 102A–5APubMedCrossRef

60.

Jardine A, Holdaas H. Fluvastatin in combination with cyclosporine in renal transplant recipients: a review of clinical safety and experience. J Clin Pharm Ther 1999; 24: 397–408PubMedCrossRef

61.

Garnett WR, Venitz J, Wilkens RC, et al. Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin. Am J Med 1994; 96(6A): 84S–86SPubMedCrossRef

62.

Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62: 1559–64PubMedCrossRef

63.

Williamson KM, Patterson JH, McQueen RH, et al. Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998; 63: 316–23PubMedCrossRef

64.

Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 1998; 80: 1–34PubMedCrossRef

65.

Tanigawara Y, Okamura N, Hirai M, et al. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 1992; 263: 840–5PubMed

66.

Su S, Huang J. Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab Dispos 1996; 24: 142–7PubMed

67.

Yu DK. The contribution of p-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 1999; 39: 1203–11PubMedCrossRef

68.

Boyd RA, Stern RH, Stewart BH. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal p-glycoprotein-mediated secretion. J Clin Pharmacol 2000;40:91–8PubMedCrossRef

69.

Lindahl A, Sandstrom R, Ungell AL, et al. Concentration and region-dependent intestinal permeability of fluvastatin in the rat. J Pharm Pharmacol 1998; 50: 737–44PubMedCrossRef

70.

Leeman T, Transon C, Bonnabry P, et al. A major role for cytochrome P450TB (CYP2C9 subfamily) in the actions of nonsteroidal antiinflammatory drugs. Drugs Exp Clin Res 1993; 19: 189–95

71.

Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32(3): 210–58PubMedCrossRef

72.

Appel S, Dingemanse J. Pharmacokinetic and pharmacodynamic interactions of fluvastatin and their therapeutic implications. Rev Contemp Pharmacother 1996; 7: 167–82

73.

Kline SS, Harrell CC. Potential warfarin-fluvastatin interaction [letter]. Ann Pharmacother 1997; 31(6): 79

74.

Trilli LE, Kelley CL, Aspinall Sl, et al. Potential interaction between warfarin and fluvastatin. Ann Pharmacother 1996; 30: 1399–402PubMed

75.

Kazierad DJ, Martin DE, Blum RA, et al. Effect of fluconazole on the pharmcokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 1997; 62(4): 417–25PubMedCrossRef

76.

Parnell K, Rodgers J, Graff D, et al. Inhibitory effect of fluconazole (FLC) and erythromycin (ERY) plus fluvastatin (FLV) on losartan (L) disposition in normal volunteers [abstract]. Clin Pharmacol Ther 2000; 67(2): PII–25

Title: Clinical Pharmacokinetics of Fluvastatin
Authors: Charity D. Scripture
Professor John A. Pieper
Publication date: 01-04-2001
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 4/2001
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200140040-00003

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clinical Pharmacokinetics of Fluvastatin

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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