Skip to main content
Log in

Pharmacodynamics and Pharmacokinetics of the HMG-CoA Reductase Inhibitors

Similarities and Differences

Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level.

The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoAto mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance.

There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins.

The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDLcatabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins.

Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised.

The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (>90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Superko HR, Krauss MR. Coronary artery disease regression — convincing evidence for the benefit of aggressive lipoprotein management. Circulation 1994; 90: 1056–69

    PubMed  CAS  Google Scholar 

  2. Levine GN, Keaney Jr JF, Vita JA. Cholesterol reduction in cardiovascular disease — clinical benefits and possible mechanisms. N Engl J Med 1995; 332: 512–21

    PubMed  CAS  Google Scholar 

  3. Gotto AM. Lipid lowering, regression, and coronary events — a review of the interdisciplinary council on lipids and cardiovascular risk intervention, Seventh Council meeting. Circulation 1995; 92: 647–56

    Google Scholar 

  4. Brown BG, Zhao XQ, Sacco DE, et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993; 87: 1781–91

    PubMed  CAS  Google Scholar 

  5. Holme I. Cholesterol reduction and its impact on coronary artery disease and total mortality. Am J Cardiol 1995; 76: 10C–17C

    PubMed  CAS  Google Scholar 

  6. Pedersen TR, Kjekshus J, Berg K, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S) Lancet 1994; 344: 1383–9

    Google Scholar 

  7. Shepherd J, Cobbe SM, Ford I, et al. for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  9. Holme I. An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation 1990; 82: 1916–24

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  11. Sirtori CR. Tissue selectivity of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Pharmacol Ther 1993; 60: 431–59

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  13. Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B and ML-236C. New inhibitors of cholesterogenesis produced by Penicillium cit5rinum. J Antibiot 1976; 29: 1346–8

    PubMed  CAS  Google Scholar 

  14. Alberts AW, Chen J, Kuron G, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 1980; 77: 3957–61

    PubMed  CAS  Google Scholar 

  15. Hoffman WF, Alberts AW, Anderson PS, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: 4. Side chain ester derivatives of mevinolin. J Med Chem 1986; 29: 849–52

    PubMed  CAS  Google Scholar 

  16. Nakaya N, Homma Y, Tamachi H, et al. The effect of CS-514 on serum lipids and apolipoproteins in hypercholesterolemic subjects. JAMA 1987; 257: 3088–93

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  20. 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; 11:519–31

    PubMed  CAS  Google Scholar 

  21. Serajuddin ATM, Ranadive SA, Mahoney EM, et al. Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. J Pharm Sci 1991; 80: 830–34

    PubMed  CAS  Google Scholar 

  22. Garnett WR. The pharmacology of fluvastatin, a new HMGCoA reductase inhibitor. Clin Cardiol 1994; 17 Suppl. IV IV–3–IV–10

    Google Scholar 

  23. Cilla Jr DD, Whitfield LR, Gibson DM, et al. Multiple-dose pharmacokinetics, pharmacodynamics and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin Pharmacol Ther 1996; 60(6): 687–695

    PubMed  CAS  Google Scholar 

  24. Mitchel YB. The long-term tolerability profile of lovastatin and simvastatin. Atherosclerosis 1992; 97: S33–S39

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  26. Fager G. The clinical documentation of fluvastatin. Astra Hässle AB, 1995

  27. Jacotot B, Benghozi R, Pfister P, et al. Comparison of fluvastatin versus pravastatin treatment of primary hypercholesterolemia. Am J Cardiol 1995; 76: 54A-56A

    Google Scholar 

  28. Haasis R, Berger J. Fluvastatin versus lovastatin — eine randomisierte, doppelblinde, multizentrische parallel gruppen studie zur effektivität und Sicherheit einer lipdsenkung. Herz Kreislauf 1995; 27: 375–80

    Google Scholar 

  29. Schulte K-L, Beil S. Efficacy and tolerability of fluvastatin and simvastatin in hypercholesterolaemic patients: a double-blind, randomised, parallel-group comparison. Clin Drug Invest 1996; 12: 119–26

    CAS  Google Scholar 

  30. Ose L, Scott R, Simvastatin-Fluvastatin Study Group. Double-blind comparison of the efficacy and tolerability of simvastatin and fluvastatin in patients with primary hypercholesterolaemia. Clin Drug Invest 1995; 10: 127–38

    CAS  Google Scholar 

  31. Illingworth DR, Sten EA, Knopp RH, et al. A randomized multicenter trial comparing the efficacy of simvastatin and fluvastatin. J Cardiovasc Pharmacol Ther 1996; 1: 23–30

    PubMed  CAS  Google Scholar 

  32. Desplypere JP. Simvastatin-fluvastatin comparative study. Clin Drug Invest 1996; 11:362–63

    Google Scholar 

  33. Deslypere JP. Simvastatin-fluvastatin comparative study — contined [letter]. Clin Drug Invest 1996; 12: 57

    Google Scholar 

  34. Haasis R, Berger J, Andersson F, et al. A pharmacoeconomic evaluation of fluvastatin and lovastatin in primary hypercholesterolaemia. Br J Med Econ 1996; 10: 145–57

    Google Scholar 

  35. Herd JA, Ballantyne CM, Farmer JA. The effect of fluvastatin on coronary atherosclerosis: the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Circulation 1996; 94 Suppl.: abstract 3496

    Google Scholar 

  36. Barr WH. The role of intestinal metabolism on bioavailability. In: Welling PG, Tse FLS, Dighe SV, editors. Pharmaceutical bioequivalence. New York: Marcel Dekker, 1991: 149–68

    Google Scholar 

  37. De Waziers I, Cugnenc PH, Yang CS, et al. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferase in rat and human hepatic and extrahepatic tissues. J Pharmacol ExpTher 1990; 253: 387–94

    Google Scholar 

  38. Kyvöstö KT, Boojkans G, Fromm MF, et al. Expression of CYP 3A4, CYP 3A5 and CYP 3A7 in human duodenal tissue. Br J Clin Pharmacol 1996; 42: 387–9

    Google Scholar 

  39. Thummel KE, Diarmuid O’S, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1995:59:491–502

    Google Scholar 

  40. Lindahl A, Sandström R, Ungell A-L, et al. Jejunal permeability and hepatic extraction of fluvastatin in humans. Clin Pharmacol Ther 1996; 60: 493–503

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  42. Tse FLS, Dain JG, Kalafsky G. Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae. Biopharm Drug Dispos 1995; 16: 211–9

    PubMed  CAS  Google Scholar 

  43. Transon C, Leemann T, Dayer P, et al. Selective in vitro inhibition profile by fluvastatin indicates its potential in vivo drug interactions. Clin Pharmacol Ther 1993; abstract PII-74

  44. Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMGCoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15

    PubMed  CAS  Google Scholar 

  45. Smith HT, Jokubaitis LA, Troendle AJ, et al. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens 1993; 6: 17–26

    Google Scholar 

  46. Lennernäs H, Ahrenstedt Ö, Hällgren R, et al. Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm Res 1992; 9: 1243–51

    PubMed  Google Scholar 

  47. Duggan DE, Chen I-W, Bayne WF, et al. The physiological disposition of lovastatin. Drug Metab Dispos 1988; 17: 166–73

    Google Scholar 

  48. Wils P, Warnery A, Phung-Ba V, et al. High lipophilicity decreases drug transport across intestinal epithelial cells. J Pharmacol Exp Ther 1994; 269: 1268–77

    Google Scholar 

  49. Dimitroulakos J, Yeger H. HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein expressing cells. Nature Med 1996; 2: 326–33

    PubMed  CAS  Google Scholar 

  50. Schinkel AH, Smit JJM, Tellingen van O, et al. Disruption of the mouse mdr la P-glycoprotein gene leads to deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502

    PubMed  CAS  Google Scholar 

  51. Leveilie-Webster CR, Arias IM. The biology of the P-glycoproteins. J Membr Biol 1995; 143: 89–102

    Google Scholar 

  52. Pan HY, DeVault AR, Wang-Iverson D, et al. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J Clin Pharmacol 1990; 30: 1128–35

    PubMed  CAS  Google Scholar 

  53. Pan HY. Clinical pharmacology of pravastatin, a selective inhibitor of HMG-CoA reductase. Eur J Pharmacol 1991; 40 Suppl. 1: S8–S15

    Google Scholar 

  54. Quion JAV, Jones PH. Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet 1994; 27: 94–103

    PubMed  CAS  Google Scholar 

  55. Singhvi SM, Pan HY, Morrison RA, et al. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol 1990; 29: 239–43

    PubMed  CAS  Google Scholar 

  56. Palm K, Luthman K, Ungell A-L, et al. Correlation of drug absorption with molecular surface properties. J Pharm Sci 1996; 85: 32–9

    PubMed  CAS  Google Scholar 

  57. Van de Waterbeemd H, Camenisch G, Folkers G. et al. Physicochemical models of Caco-2 transport by passive diffusion. Quant Struct Act Relat. In press

  58. Triscari J, O’Donnell D, Zinny M, et al. Gastrointestinal absorption of pravastatin in healthy subjects. J Clin Pharmacol 1995; 35: 142–4

    PubMed  CAS  Google Scholar 

  59. Vickers S, Duncan CA, Chen I-W, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos 1989; 18: 138–45

    Google Scholar 

  60. Cheng H, Sutton SC, Pipkin JD, et al. Evaluation of sustained/ controlled-release dosage forms of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors in dogs and humans. Pharm Res 1993; 10: 1683–7

    PubMed  CAS  Google Scholar 

  61. Tang B-K, Kalow W. Variable activation of lovastatin by hydrolytic enzymes in human plasma and liver. Eur J Clin Pharmacol 1995; 47: 449–51

    PubMed  CAS  Google Scholar 

  62. Rowland M, Tozer T. Clinical pharmacokinetics. 2nd ed. Philadelphia (PA): Lea & Febiger, 1989

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  64. Koga T, Fukuda K, Shimada Y, et al. Lovastatin and simvastatin: the relationship between inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen, and testis in rat. Eur J Biochem 1992; 209: 315–9

    PubMed  CAS  Google Scholar 

  65. Rolan PE. Plasma protein binding displacement interactions — why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37: 125–28

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  67. Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cytochrome P450tb (CYP2C9) by (±)-fluvastatin. Clin Pharmacol Ther 1995; 58: 412–7

    PubMed  CAS  Google Scholar 

  68. Lennernäs H, Regårdh CG. Dose-dependent intestinal absorption and significant intestinal excretion (exsorption) of the β-blocker pafenolol in the rat. Pharm Res 1993; 10: 727–31

    PubMed  Google Scholar 

  69. Wetterich U, Spahn-Langguth H, Mutschier E, et al. Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dosedependent absorption in vitro and in vivo. Pharm Res 1996; 13:514–22

    PubMed  CAS  Google Scholar 

  70. Everett DW, Chando TJ, Didonato GC, et al. Biotransformation of pravastatin sodium in humans. Drug Metab Dispos 1991; 19:740–8

    PubMed  CAS  Google Scholar 

  71. 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

    PubMed  CAS  Google Scholar 

  72. Duggan DE, Vickers S. Physiological disposition of HMGCoA-reductase inhibitors. Drug Metab Rev 1990; 22: 333–62

    PubMed  CAS  Google Scholar 

  73. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202

    PubMed  CAS  Google Scholar 

  74. Wang RW, Karl PH, Lu AYH, et al. Biotransformation of lovastatin. IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 1991; 290: 355–61

    PubMed  CAS  Google Scholar 

  75. Cheng H, Rogers JD, Sweany AE, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm Res 1992; 9: 1629–34

    PubMed  CAS  Google Scholar 

  76. Vyas KP, Kari PH, Pitzenberger SM. Regioselectivity and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 1990; 166: 1155–62

    PubMed  CAS  Google Scholar 

  77. Simvastatin manufacturing information. US: Merck & Co. Inc., 1991

  78. Mckenney JM. Lovastatin: a new cholesterol-lowering agent. Clin Pharm 1988; 7: 21–38

    PubMed  CAS  Google Scholar 

  79. Holtzman JL, Finley DK, Zhou LX, et al. Interaction between isradipine and lovastatin in normal male volunteers. Clin Pharmacol Ther 1993; abstract PI-116

  80. Stein WD. Transport and diffusion across cell membranes. New York: Academic Press, 1986

    Google Scholar 

  81. Germershausen JI, Hunt VM, Bostedor RG, et al. Tissue selectivity of the cholesterol-lowering agents lovastatin, simvastatin and pravastatin in rats in vivo. Biochem Biophys Res Commun 1989; 158: 667–75

    PubMed  CAS  Google Scholar 

  82. Komai T, Shigehara E, Tokui T, et al. Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture. Biochem Pharmacol 1992; 43: 667–70

    PubMed  CAS  Google Scholar 

  83. Sathirakul K, Suzuki H, Yamada T, et al. Multiple transport systems for organic anions across the bile canalicular membrane. J Pharmacol Exp Ther 1993; 268: 65–72

    Google Scholar 

  84. Shaw MK, Newton RS, Sliskovic DR. Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase. Biochem Biophys Res Commun 1990; 170:726–34

    PubMed  CAS  Google Scholar 

  85. Yamazaki M, Suzuki H, Hanano M, et al. Na+-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am J Physiol 1993; 264: G36–44

    PubMed  CAS  Google Scholar 

  86. Ziegler K, Hummelsiep S. Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone. Biochim Biophys Acta 1993; 1153: 23–33

    PubMed  CAS  Google Scholar 

  87. Yamazaki M, Akiyama S, Nishigaki R, et al. Uptake is the ratelimiting step in the overall hepatic elimination of pravastatin at steady-state in rats. Pharm Res 1996; 13: 1559–64

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  89. Saheki A, Terasaki T, Tamai I, et al. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res 1994; 11:305–11

    PubMed  CAS  Google Scholar 

  90. Tsuji A, Saheki A, Tamai I, et al. Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier. J Pharmacol Exp Ther 1993; 267: 1085–90

    PubMed  CAS  Google Scholar 

  91. Eckernäs S-Å, Roos B-E, Kvidal P, et al. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993; 35: 284–9

    PubMed  Google Scholar 

  92. Harrison RWS, Ashton CH. Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers. Br J Clin Pharmacol 1994; 37:231–6

    PubMed  CAS  Google Scholar 

  93. Pan HY, Waclawski AP, Funke PT, et al. Pharmacokinetics of pravastatin in elderly versus young men and women. Ann Pharmacother 1993; 27: 1029–33

    PubMed  CAS  Google Scholar 

  94. Smit JWA, Wijne HJA, Schobben F, et al. Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin. Am J Cardiol 1995; 76: 89A-96A

    Google Scholar 

  95. Pan HY, DeVault AR, Brescia D, et al. Effect of food on pravastatin pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther Toxicol 1993; 31: 291–4

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  97. Ritcher WO, Jacob BG, Schwandt P. Interaction between fibre and lovastatin [letter]. Lancet 1991; 338: 706

    Google Scholar 

  98. Triscari J, Rossi L, Pan HY. Chronokinetics of pravastatin administered in the pm compared with am dosing. Am J Ther 1995; 2: 265–8

    PubMed  Google Scholar 

  99. Appel S, Rüfenacht 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: 29A-32A

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  101. Goldberg R, Roth D. Fluvastatin safety, efficacy and kinetics in the treatment of hypercholesterolemia in renal-transplant patients receiving cyclosporine. Proceedings of the 10th International Symposium on Atherosclerosis; 1994 Oct 9–14; Montreal: 6a-d

  102. Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am J Cardiol 1994; 73: 18D-24D

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  104. Cheng H, Rogers JD, Sweany AE, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm Res 1992; 9: 1629–34

    PubMed  CAS  Google Scholar 

  105. Pan HY, Triscari J, DeVault AR, et al. Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin. Br J Clin Pharmacol 1991; 31: 665–70

    PubMed  CAS  Google Scholar 

  106. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62: 28J-34J

    Google Scholar 

  107. Corpier CL, Jones PH, Wadi NS, et al. Rhabdomyolysis and renal injury with lovastatin use. The report of two cases in cardiac transplant recipients. JAMA 1988; 260: 239–41

    PubMed  CAS  Google Scholar 

  108. Illingworth DR, Bacon SP, Larsen KK. Long-term experience with HMG-CoA reductase inhibitors in the therapy of hypercholesterolemia. Atherosclerosis Rev 1988; 18: 46–7

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  110. Ahmad S. Lovastatin: warfarin interaction. Arch Intern Med 1990; 150:2407

    PubMed  CAS  Google Scholar 

  111. Hoffman HS. The interaction of lovastatin and warfarin. Conn Med 1992; 56: 107

    PubMed  CAS  Google Scholar 

  112. Pan HY, DeVault AR, Swites BJ, et al. Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia. Clin Pharmacol Ther 1990; 48:201–7

    PubMed  CAS  Google Scholar 

  113. Regazzi MB, Iacona I, Campana C, et al. Clinical efficacy and pharmacokinetics of HMG-CoA reductase inhibitors in heart transplant patients treated with cyclosporin A. Transplant Proc 1994; 26: 2644–5

    PubMed  CAS  Google Scholar 

  114. Meyer BH, Scholtz HE, Müller FO, et al. Lack of interaction between ramipril and simvastatin. Eur J Clin Pharmacol 1994; 47: 373–5

    PubMed  CAS  Google Scholar 

  115. Triscari J, Swanson BN, Willard DA, et al. Steady state serum concentrations of pravastatin and digoxin when given in combination. Br J Clin Pharmacol 1993; 36: 263–5

    PubMed  CAS  Google Scholar 

  116. Campana C, Iacona I, Regazzi MB, et al. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacother 1995; 29: 235–9

    PubMed  CAS  Google Scholar 

  117. Smith PF, Eydelloth RS, Grossman SJ, et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporin A interaction and mechanism studies. J Pharmacol Ther 1991; 257: 1225–35

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hans Lennernäs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lennernäs, H., Fager, G. Pharmacodynamics and Pharmacokinetics of the HMG-CoA Reductase Inhibitors. Clin-Pharmacokinet 32, 403–425 (1997). https://doi.org/10.2165/00003088-199732050-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199732050-00005

Keywords

Navigation