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Clinical Pharmacokinetics of Fibric Acid Derivatives (Fibrates)

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  • Drug Disposition
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Abstract

Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein(a), fibrinogen and uric acid.

As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment.

The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate.

Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.

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References

  1. Thorp JM, Waring WS. Modification of metabolism and distribution of lipids by ethyl chlorophenoxyisobutyrate. Nature. 1962; 194: 948–9.

    Article  PubMed  CAS  Google Scholar 

  2. Patsch JR, Miesenbock G, Hopferweiser T, et al. Relation of triglyceride metabolism and coronary artery disease: studies in the postpradnial state. Arterioscler Throbm. 1992; 12: 1336–45.

    Article  CAS  Google Scholar 

  3. Austin MA. Plasma triglyceride and coronary heart disease. Arterioscler Thromb. 1991; 11: 2–14.

    Article  PubMed  CAS  Google Scholar 

  4. Manninen V, Elo O, Frick H, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA. 1988; 260: 641–51.

    Article  PubMed  CAS  Google Scholar 

  5. Steiner G. Triglyceride-rich lipoproteins and atherosclerosis, from fast to feast. Ann Med. 1993; 25(5): 431–5.

    Article  PubMed  CAS  Google Scholar 

  6. Gronholdt ML, Nordestgaard BG, Nielsen TG, et al. Echolucent carotid artery plaques are associated with elevated levels of fasting and postprandial triglyceride-rich lipoproteins. Stroke. 1996; 27(12): 2166–72.

    Article  PubMed  CAS  Google Scholar 

  7. Vogel RA, Corretti M, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997; 79: 350–4.

    Article  PubMed  CAS  Google Scholar 

  8. Kesaniemi YA, Grundy SM. Influence of gemfibrozil on metabolism of cholesterol and plasma triglycerides in man. JAMA. 1984; 251: 2241–6.

    Article  PubMed  CAS  Google Scholar 

  9. Nikkila EA, Huttunen JK, Ehnholm C. Effect of clofibrate on postheparin plasma triglyceride lipase activities in patients with hypertriglyceridemia. Metabolism. 1977; 26: 179–86.

    Article  PubMed  CAS  Google Scholar 

  10. Nikkila EA, Ylikahri R, Huttunen JK. Gemfibrozil: effect on serum lipids, lipoproteins, postheparin plasma lipase activities and glucose tolerance in primary hypertriglyceridemia. Proc R Soc Med. 1976; 69 Suppl. 2: 58–63.

    PubMed  Google Scholar 

  11. Desager JP, Horsmans Y, Vandenplas C, et al. Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days. Atherosclerosis 1996; 124 Suppl.: S65–73.

    Article  PubMed  CAS  Google Scholar 

  12. Ooi TC, Simo IE, Yakichuk JA. Delayed clearance of postprandial chylomicrons and their remnants in the hypoalphalipoproteinemia and mild hypertriglyceridemia syndrome. Arterioscler Thromb. 1992; 12: 1184–90.

    Article  PubMed  CAS  Google Scholar 

  13. Stewart JM, Packard CJ, Lorimer AR, et al. Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinemic subjects. Atherosclerosis. 1982; 44: 355–65.

    Article  PubMed  CAS  Google Scholar 

  14. Vega GL, Grundy SM. Gemfibrozil therapy in primary hypertriglyceridemia associated with coronary heart disease: effects on metabolism of low-density lipoproteins. JAMA. 1985; 253: 2398–403.

    Article  PubMed  CAS  Google Scholar 

  15. Saku K, Gartside PS, Hynd BA, et al. Mechanism of action of gemfibrozil on lipoprotein metabolism. J Clin Invest. 1985; 75: 1702–12.

    Article  PubMed  CAS  Google Scholar 

  16. Stolley PD, Zahm SH. Nonhormonal drugs and cancer. Environ Health Perspect. 1995; 103 Suppl. 8: 191–6.

    Article  PubMed  CAS  Google Scholar 

  17. A co-operative trial in the primary prevention of ischaemic heart disease: report from the Committee of Principal Investigators. Br Heart J 1978 Oct; 40 (10): 1069–118.

  18. Larsen ML, Illingworth DR, O’Malley JP. Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia. Atherosclerosis. 1994; 106(2): 235–40.

    Article  PubMed  CAS  Google Scholar 

  19. Monk JP, Todd PA. Bezafibrate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidemia. Drugs. 1987; 33: 539–76.

    Article  PubMed  CAS  Google Scholar 

  20. Abshagen U, Kosters W, Kaufmann B, et al. Pharmacokinetics of bezafibrate after single and multiple doses in the presence of renal failure. Klin Wochenschrift. 1980; 58: 889–96.

    Article  CAS  Google Scholar 

  21. Abshagen U, Bablok W, Koch K, et al. Disposition pharmacokinetics of bezafibrate in man. Eur J Clin Pharmacol. 1979; 16: 31–8.

    Article  PubMed  CAS  Google Scholar 

  22. Shepherd J. The fibrates in clinical practice: focus on micronised fenofibrate. Atherosclerosis. 1994; 110: S55–63.

    Article  PubMed  CAS  Google Scholar 

  23. Ferry N, Bernard N, Pozet N, et al. The influence of renal insufficiency and haemodialysis on the kinetics of ciprofibrate. Br J Clin Pharmacol. 1989; 28: 675–81.

    Article  PubMed  CAS  Google Scholar 

  24. Davison C, Benziger D, Fritz A, et al. Absorption and disposition of 2-[4-(2.2-dichlorocyclopropyl)-phenoxy]-2-methyl-propanoic acid, WIN 35.833, in rats, monkeys and men. Drug Metab Dispos. 1975; 3: 520–4.

    PubMed  CAS  Google Scholar 

  25. Gugler R, Shoeman DW, Huffman DH, et al. Pharmacokinetics of drugs in patients with nephrotic syndrome. J Clin Invest. 1975; 55: 1182–9.

    Article  PubMed  CAS  Google Scholar 

  26. Balfour JA, McTavish D, Heel RC. Fenofibrate: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs. 1990; 40: 260–90.

    Article  PubMed  CAS  Google Scholar 

  27. Desager JP, Costermans J, Verberckmoes R, et al. Effect of hemodialysis on plasma kinetics of fenofibrate in chronic renal failure. Nephron. 1982; 31: 51–4.

    Article  PubMed  CAS  Google Scholar 

  28. Strolin Benedetti M, Guichard JP, Vidal R, et al. Kinetics and metabolic fate of 14C-fenofibrate in human plasma. Acta Pharmacol Toxicol. 1986; 59 Suppl. 5: 167.

    Google Scholar 

  29. Desager JP, Harvengt C. Clinical pharmacokinetic study of procetofene, a new hypolipidemic drug, in volunteers. Int J Clin Pharmacol Biopharm. 1978; 16: 570–4.

    PubMed  CAS  Google Scholar 

  30. Munoz A, Guichard JP, Reginault P. Micronised fenofibrate. Atherosclerosis. 1994; 110: S45–8.

    Article  Google Scholar 

  31. Hamberger C, Barre J, Zini R, et al. In vitro binding study of gemfibrozil to human serum proteins and erythrocytes: interactions with other drugs. Int J Clin Pharmacol Res. 1986; 6: 441–9.

    PubMed  CAS  Google Scholar 

  32. US pharmacopoeia drug information; Vol. 1. Drug information for the health care professional. 12th ed. Rockville (MD): US Pharmacopeial Convention, 1992.

    Google Scholar 

  33. Vens-Cappell B, Berndt P, Hilgenstock C, et al. Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. II: multiple-dose administration and chronopharmacokinetics. Arzneimittel Forschung. 1993; 43: 351–6.

    CAS  Google Scholar 

  34. Vens-Cappell B, Hilgenstock C, Geliert M, et al. Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. I: single-dose administration. Arzneimittel Forschung. 1993; 43: 346–50.

    CAS  Google Scholar 

  35. Guichard JP, Levy-Prades Sauron R. A comparison of the bioavailability of standard or micronized formulations of fenofibrate. Curr Ther Res. 1993; 54: 610–4.

    Article  Google Scholar 

  36. Lipidil product monograph. Fournier Pharma Inc., Montreal (Canada), 1990.

  37. Cook JA, Rajagopalan R, Eldon MA, et al. Effect of time of dosing on the pharmacokinetics of a controlled-release gemfibrozil tablet (Lopid SR). Pharmacol Res 1991; 8 Suppl.: S296.

    Google Scholar 

  38. Cook JA, Eldon MA, Gibson DM, et al. Gemfibrozil pharmacokinetics after multiple-dose administration of controlledrelease (Lopid SR) and conventional (Lopid) tablets. Pharmacol Res 1992; 9 Suppl.: S325.

    Google Scholar 

  39. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drugs and food [see comments in: ACP J Club 1995; 122 (2): 44]. Ann Intern Med. 1994; 121(9): 676–83.

    PubMed  CAS  Google Scholar 

  40. Todd PA, Ward A. Gemfibrozil: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidemia. Drugs. 1988; 36: 314–39.

    Article  PubMed  CAS  Google Scholar 

  41. Ahmad S. Gemfibrozil interaction with warfarin sodium (coumadin). Chest. 1990; 98: 1041–2.

    Article  PubMed  CAS  Google Scholar 

  42. Blum A, Livneh A, Seligmann H. Severe gastrointestinal bleeding induced by a probable hydroxycoumarin-bezafibrate interaction. Isr J Med Sci. 1992; 28: 47–9.

    PubMed  CAS  Google Scholar 

  43. Ferrari C, Romussu M, Testori GP, et al. Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus. Biomedicine. 1978; 29: 133–6.

    PubMed  CAS  Google Scholar 

  44. Brown MS, Goldstein JL. Drugs used in the treatment of hyerlipoproteinemias. In: Gilman AG, editor. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon, 1990: 886–9.

    Google Scholar 

  45. Ahmad S. Gemfibrozil: interaction with glyburide. South Med J. 1991; 84: 102.

    Article  PubMed  CAS  Google Scholar 

  46. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990; 264: 71–5.

    Article  PubMed  CAS  Google Scholar 

  47. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. Eur Heart J. 1995; 16: 5–13.

    Article  PubMed  CAS  Google Scholar 

  48. Spence JD, Munoz CE, Hendricks L. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol. 1995; 76: 80–3.

    Article  Google Scholar 

  49. Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm. 1995; 52(15): 1639–45.

    PubMed  CAS  Google Scholar 

  50. Neuvonen PJ, Jalava K-M. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1996; 60: 54–61.

    Article  PubMed  CAS  Google Scholar 

  51. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporinetreated kidney graft patients after multiple doses. Clin Pharmacol Ther. 1997; 62: 311–21.

    Article  PubMed  CAS  Google Scholar 

  52. Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cyctochrome P450TB (CYP2C9) by (+/−)-fluvastatin. Clin Pharmacol Ther. 1995; 58(4): 412–7.

    Article  PubMed  CAS  Google Scholar 

  53. Kitazawa E, Tamura N, Iwabuchi H, et al. Biotransformation of pravastatin sodium (I): mechanisms of enzymic transformation and epimerization of an allylic hydroxy group of pravastatin sodium. Biochem Biophys Res Commun. 1993; 192: 597–602.

    Article  PubMed  CAS  Google Scholar 

  54. Spence JD. Drug interactions with grapefruit: whose responsibility is it to warn the public? Clin Pharmacol Ther. 1997; 61: 395–400.

    Article  PubMed  CAS  Google Scholar 

  55. Corpier CI, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA. 1988; 260: 239–41.

    Article  PubMed  CAS  Google Scholar 

  56. East C, Alivizatos PA, Grundy SC, et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med. 1988; 318: 47–8.

    Article  PubMed  CAS  Google Scholar 

  57. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995; 333: 664–5.

    Article  PubMed  CAS  Google Scholar 

  58. Liedholm H, Nordin G. Erythromycin-felodipine interaction. Drug Intell Clin Pharmacol. 1991; 25: 1007–8.

    CAS  Google Scholar 

  59. Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med. 1995; 333: 628–33.

    Article  PubMed  CAS  Google Scholar 

  60. Bailey DG, Spence JD, Munoz C, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet. 1991; 337: 268–9.

    Article  PubMed  CAS  Google Scholar 

  61. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokinet. 1994; 26(2): 91–8.

    Article  PubMed  CAS  Google Scholar 

  62. Rau SE, Bend JR, Arnold MO, et al. Grapefruit juice: terfenadine single-dose interaction: magnitude, mechanism, and relevance. Pharmacokinet Drug Dispos. 1997; 61: 401–9.

    CAS  Google Scholar 

  63. Bailey DG, Bend JR, Arnold JMO, et al. Erythromycin-felodipine interaction: magnitude, mechanism and comparison with grapefruit juice. Clin Pharmacol Ther 1996 Jul; 60(1): 25–33.

    Article  PubMed  CAS  Google Scholar 

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  1. Stroke Prevention and Atherosclerosis Research Centre, Siebens-Drake Research Building, Robarts Research Institute and The University of Western Ontario, 1400 Western Road, London, Ontario, N6G 2V2, Canada

    David B. Miller &  J. David Spence

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Miller, D.B., Spence, J.D. Clinical Pharmacokinetics of Fibric Acid Derivatives (Fibrates). Clin Pharmacokinet 34, 155–162 (1998). https://doi.org/10.2165/00003088-199834020-00003

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