Summary
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of cholesterol synthesis. HMG-CoA reductase inhibitors are potent reversible inhibitors of this enzyme, which act by competing for the substrate HMG-CoA.
This review is mainly devoted to the 4 main HMG-CoA reductase inhibitors used today: lovastatin, simvastatin, pravastatin and fluvastatin. Depending upon the dosage, these drugs are able to reduce plasma cholesterol levels by more than 40%. After absorption, each undergoes extensive hepatic first-pass metabolism. Up to 5 primary metabolites are formed, some of which are active inhibitors. The elimination half-lives vary from 0.5 to 3.5 hours and excretion is mainly via the faeces. A limited number of drug interactions has been reported. Increases in liver enzymes and muscle creatine kinase activity are among the most severe adverse effects.
These powerful drugs should be reserved for patients with high plasma cholesterol levels and/or those with cardiovascular disease.
New therapeutic approaches to atherosclerosis are currently under investigation. HMG-CoA reductase inhibitors are the cornerstone of this research.
Similar content being viewed by others
References
Kannel WB, Dawber TR, Kagan A, et al. Factors of risk in the development of coronary heart disease — six year follow-up experience: the Framingham Study. Ann Intern Med 1961; 55: 33–50
Grundy SM, Ahrens EH, Davignon J. The interaction of cholesterol absorption and cholesterol synthesis in man. J Lipid Res 1969; 10: 304–15
Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992; 33: 1569–82
Luskey KL. Regulation of cholesterol synthesis: mechanism for control of HMG CoA reductase. Recent Prog Horm Res 1988; 44: 35–51
Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425–30
Thompson GR. A handbook of hyperlipidaemia. London: Current Science Ltd, 1989
Packard CJ, Munro A, Lorimer AR, et al. Metabolism of apolipoprotein B in large triglyderide-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J Clin Invest 1984; 74: 2178–92
Watts GF, Mandalia S, Brunt JNH, et al. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas’ atherosclerosis regression study (STARS). Metabolism 1993; 42: 1461–7
Treadwell CR, Vahouny GV. Cholesterol absorption. Am Physiol Soc 1968; III: 1407–38
Glomset JA. The plasma lecithin: cholesterol acyltransferase reaction. J Lipid Res 1968; 9: 155–67
Berg K. Lp(a) lipoprotein: an overview. Chem Phys Lipids 1994; 67/68: 9–16
Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. Lipid Res 1995; 36: 211–28
Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res 1993; 34: 1255–74
Keys A, Menotti A, Aravanis C, et al. The seven countries study: 2,289 deaths in 15 years. Prev Med 1984; 13: 141–54
Adult Treatment Pannel II. National Cholesterol Education Program: second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Cirulation 1994; 89: 1333–45
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. N Engl J Med 1967; 276: 148–56
Alaupovic P. Apolipoproteins and lipoproteins. Atherosclerosis 1971; 13: 141–96
Chait A, Brunzell JD. Acquired hyperlipidemia (secondary dyslipoproteinemias). Endocrinol Metab Clin North Am 1990; 19: 259–78
Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am 1994; 78: 117–41
Havel RJ, Rapaport E. Management of primary hyperlipidemia. N Engl J Med 1995; 332: 1491–8
Henwood JM, Heel RC. Lovastatin: a preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. Drugs 1988; 36: 429–54
Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res 1995; 31: 9–27
Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 1976; 72: 323–6
Brown MS, Faust JR, Goldstein JL, et al. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J Biol Chem 1978; 253: 1121–8
Chin KJ, Luskey KL, Anderson RGW, et al. Appearance of crystalloid endoplasmic reticulum in compactin resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A 1982; 79: 1185–9
Bélichard P, Pruneau D, Zhiri A. Effect of a long-term treatment with lovastatin or fenofibrate on hepatic and cardiac ubiquinone levels in cardiomyopathic hamster. Biochim Biophys Acta 1993; 1169: 98–102
Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 1990; 87: 8931–4
Pogue DH, Moravec CS, Roppelt C, et al. Effect of lovastatin on cholesterol content of cardiac and red blood cell membranes in normal and cardiomyopathic hamsters. J Pharmacol Exp Ther 1995; 273: 863–9
Nielsen LB, Stender S, Kjeldsen K. Effect of lovastatin on cholesterol absorption in cholesterol-fed rabbits. Pharmacol Toxicol 1993; 72: 148–51
Ishida F, Sato A, Iizuka Y, et al. Inhibition of acyl coenzyme A: cholesterol acyltransferase by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Chem Pharm Bull (Tokyo) 1989; 37: 1635–6
La Ville AE, Seddon AM, Shaikh M, et al. Primary prevention of atherosclerosis by lovastatin in a genetically hyperlipidaemic rabbit strain. Atherosclerosis 1989; 78: 205–10
Tobert JA, Bell GD, Birtwell J, et al. Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, in healthy volunteers. J Clin Invest 1982; 69: 913–9
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
Todd PA, Goa KL. Simvastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 1990; 40: 583–607
Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995; 57: 62–6
Ishida F, Sato A, Iizuka Y, et al. Effects of MK-733, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on absorption and excretion of [3H]cholesterol in rabbits. Biochim Biophys Acta 1988; 963: 35–41
Ishida F, Sato A, Iizuka Y, et al. Effects of MK-733 (simvastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme Areductase, on intestinal acylcoenzyme A: cholesterol acyltransferase activity in rabbits. Biochim Biophys Acta 1989; 1004: 117–23
Kobayashi M, Ishida F, Takahashi T, et al. Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits. Jpn J Pharmacol 1989; 49: 125–33
Ishida F, Watanabe K, Sato A, et al. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta 1990; 1042: 365–73
Malmendier CL, Lontie JF, Delcroix C, et al. Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers. Atherosclerosis 1989; 80: 101–9
Ahnadi CE, Berthezène F, Ponsin G. Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects. Atherosclerosis 1993; 99: 219–28
Horsmans Y, Desager JP, Van Den Berge V, et al. Effects of simvastatin and pravastatin on 6β-hydroxycortisol excretion, a potential marker of cytochrome P-450 3A. Pharmacol Res 1993; 28: 243–8
Gerson RJ, MacDonald JS, Alberts AW, et al. Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. Am J Med 1989; 87 Suppl. 4A: 28S-38S
Horsmans Y, Desager JP, Harvengt C. Biochemical changes and morphological alterations of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor). Pharmacol Toxicol 1990; 67: 336–9
Mercenne F, Goudonnet H, Mounie J, et al. Effects of simvastatin, a lipoprotein-lowering drug, on the hepatic enzymes involved in drug metabolism in the Wistar rat. Xenobiotica 1991; 21: 859–64
Matsuoka T, Miyakoshi S, Tanzawa K, et al. Purification and characterization of cytochrome P-450sca from Streptomyces carbophilus. Eur J Biochem 1989; 194: 707–13
Serizawa N, Matsuoka T. A two component-type cytochrome P-450 monooxygenase system in a prokaryote that catalyzes hydroxylation of ML-236B to pravastatin, a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Biochim Biophys Acta 1991; 1084: 35–40
Tsujita Y, Kuroda M, Shimada Y, et al. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reduc-tase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biophys Acta 1986; 877: 50–60
McTavish D, Sorkin EM. Pravastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 1991; 42: 65–89
Koga T, Shimada Y, Kuroda M, et al. Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Biochim Biophys Acta 1990; 1045: 115–20
Reihnér E, Rudling M, Stahlberg D, et al. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 1990; 323: 224–8
Elmberger PG, Kalén A, Lund E, et al. Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolaemia. J Lipid Res 1991; 32: 935–40
Lijnen P, Celis H, Fagard R, et al. Influence of cholesterol lowering on plasma membrane lipids and cationic transport systems. J Hypertension 1994; 12: 59–64
Lijnen P, Petrov V, Amery A. Pravastatin has no direct effect on transmembrane cationic transport systems in human erythrocytes and platelets. Eur J Clin Pharmacol 1994; 47: 281–3
Ziegler K, Stünkel W. Tissue-selective action of pravastatin due to hepatocellular uptake via a sodium-independent bile acid transporter. Biochim Biophys Acta 1992; 1139: 203–9
Takeda Y, Miyamori I, Karayalçin Ü, et al. Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, on corticosteroid metabolism in patients with heterozygous familial hypercholesterolemia. Horm Res 1991; 36: 75–7
Pan HY, De Vault AR, Wang-Iverson D, et al. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J Clin Pharmacol 1990; 30: 1128–35
Plosker GL, Wagstaff AJ. Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolemia. Drugs 1996; 51: 433–59
Corsini A, Mazzotti M, Raiteri M, et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993; 101: 117–25
Dain JG, Fu E, Gorski J, et al. Biotransformation of fluvastatin sodium in humans. Drug Metab Dispos 1993; 21: 567–72
Cheng H, Rogers JD, Sweany AE, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm Res 1992; 9: 1629–33
Quérin S, Lambert R, Cusson JR, et al. Single-dose pharmacokinetics of 14C-lovastatin in chronic renal failure. Clin Pharmacol Ther 1991; 50: 437–41
Botti RE, Triscari J, Pan HY, et al. Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacol 1991; 14: 256–61
Pentikainen PJ, Saraheimo M, Schwartz JI, et al. Comparative pharmacokinetics of lovastatin, simvastatin and pravastatin in humans. J Clin Pharmacol 1992; 32: 136–40
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
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
Cheng H, Schwartz MS, Vickers S, et al. Metabolic disposition of simvastatin in patients with T-tube drainage. Drug Metab Dispos 1994; 22: 139–42
Arnadottir M, Eriksson LO, Thysell H, et al. Plasma concentration profiles of simvastatin 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65: 410–3
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
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
Sasahara K, Kawabata K, Nakaya N, et al. Phase I study of CS-514, an inhibitor of HMG-CoA reductase. II: pharmacokinetics of CS-514 in healthy volunteers. J Clin Ther Med 1988; 4: 45–65
Halstenson CE, Triscari J, DeVault A, et al. Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment. J Clin Pharmacol 1992; 32: 124–32
Tse FLS, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 1992; 32: 630–8
Smith HT, Jokubaitis LA, Troendle AJ, et al. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens 1993; 6: 375S–82S
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
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
Funke PT, Ivashkiv E, Arnold ME, et al. Determination of pravastatin sodium and its major metabolites in human serum/plasma by capillary gas chromatography/negative ion chemical ionization mass spectrometry. Biomed Mass Spectrom 1989; 18: 904–9
Carlucci G, Mazzeo P, Biordi L, et al. Simultaneous determination of simvastatin and its hydroxy acid form in human plasma by high-performance liquid chromatography with UV detection. J Pharm Biomed Anal 1992; 10: 693–7
Whigan DB, Ivashkiv E, Cohen AI, et al. Determination of pravastatin sodium and its isomeric metabolite in human urine by HPLC with UV detection. J Pharm Biomed Anal 1989; 7: 907–12
Dumousseaux C, Muramatsu S, Takasaki W, et al. Highly sensitive and specific determination of pravastatin sodium in plasma by high-performance liquid chromatography with laser-induced fluorescence detection after immobilized antibody extraction. J Pharm Sci 1994; 83: 1630–6
Kalafsky G, Smith HT. High-performance liquid Chromatographie method for the determination of fluvastatin in human plasma. J Chromatogr 1993; 614: 307–13
Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202
Blum CB. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol 1994; 73: 3D–11D
Serajuddin ATM, Ranadive SA, Mahoney EM. Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylgluaryI-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. J Pharm Sci 1991; 80: 830–4
Triscari J, O’Donnell D, Zinny M, et al. Gastrointestinal absorption of pravastatin in healthy subjects. J Clin Pharmacol 1995; 35: 142–4
Duggan DE, Chen IW, Bayne WF, et al. The physiological disposition of lovastatin. Drug Metab Dispos 1989; 17: 166–73
Germerhausen 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
Vickers S, Duncan CA, Chen IW, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos 1990; 18: 138–45
Pan H, Fleiss P, Moore L, et al. Excretion of pravastatin, an HMG CoA reductase inhibitor, in breast milk of lactating women [abstract]. J Clin Pharmacol 1988; 28: 942
Tse FLS, Nickerson DF, Yardley WS. Blood and plasma protein binding of fluvastatin [abstract]. Int J Clin Pharmacol Ther Toxicol 1992; 30: 305–6
Duggan DE, Vickers S. Physiological disposition of HMG-CoA-reductase inhibitors. Drug Metab Rev 1990; 22: 333–62
Kaufman MJ. Rate and equilibrium constants for acid-catalyzed lactone hydrolysis of HMG-CoA reductase inhibitors. Int J Pharm 1990; 66: 97–106
Vyas KP, Kari PH, Pitzenberger SM, et al. Identification of 3′5′-dihydro-3′5′-diol-D4-lovastatin as a new cytochrome P450 3A catalyzed metabolite of lovastatin in rat and human liver microsomes [abstract]. International Society for the Study of Xenobiotics. Proceedings of the Fifth North American Meeting: 1993 Oct 17–21; Tuscon, Arizona
Vyas KP, Kari PH, Wang RW, et al. Biotransformation of lovastatin-III. Effect of cimetidine and famotidine on in vitro metabolism of lovastatin by rat and human liver microsomes. Biochem Pharmacol 1990; 39: 67–73
Wang RW, Kari 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
Regazzi MB, Iacona I, Campana C, et al. Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients. Transplant Proc 1993; 25: 2732–4
Transon C, Leemann T, Dayer P. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (±)-fluvastatin. Clin Pharmacol Ther 1995; 58: 412–7
Li PKT, Mak TWL, Wang AYM, et al. The interaction of fluvastatin and cyclosporin A in renal transplant patients. Int J Clin Pharmacol Ther 1995; 33: 246–8
St Peter JV, Braeckman RA, Granneman GR, et al. The effect of zileuton on antipyrine and indocyanine green disposition. Clin Pharmacol Ther 1995; 57: 299–308
Richter WO, Jacob BG, Schwandt P. Interaction between fibre and lovastatin [letter]. Lancet 1991; 338: 706
Deslypere JP. Clinical implications of the biopharmaceutical properties of fluvastatin. Am J Cardiol 1994; 73: 12D–17D
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-40S
Smit JW, Wijnne HJ, Schobben F, et al. Effects of alcohol and fluvastatin on lipid metabolism and hepatic function. Ann Intern Med 1995; 122: 678–80
Kuhn P, Darioli R, Bovet P et al. Dose-dependent lipid-lowering effects of simvastatin (MK-733) in the elderly. Curr Ther Res 1989; 46: 381–9
Illingworth DR, Tobert JA. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin Ther 1994; 16: 366–85
Desager JP, Horsmans Y, Harvengt C. Lecithin: cholesterol acyltransferase activity in familial hypercholesterolemia treated with simvastatin and simvastatin plus low-dose colestipol. J Clin Pharmacol 1991; 31: 537–42
Ito H, Naito C, Hayashi H, et al. Activity of low-density lipoprotein receptors as estimated from concentrations of apolipoprotein B and C-II in serum. Clin Chem 1988; 34: 2224–7
Horsmans Y, Desager JP, Harvengt C. Effects of combined bezafibrate-simvastatin appraised in healthy subjects. J Clin Pharmacol 1992; 32: 422–6
Leclercq V, Harvengt C. Simvastatin (MK 733) in heterozygous familial hypercholesterolemia: a two-year trial. Int J Clin Pharmacol Ther Toxicol 1989; 27: 76–81
The Simvastatin Pravastatin Study Group. Comparison of the efficacy, safety and tolerability of simvastatin and pravastatin for hypercholesterolemia. Am J Cardiol 1993; 71: 1408–14
Yuan JN, Tsai MY, Hegland J, et al. Effects of fluvastatin (XU 62-320), an HMG-Co A reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis 1991; 87: 147–57
Guerin M, Dolphin PJ, Talussot C, et al. Pravastatin modulates cholesteryl ester transfer from HDL to Apo B-containing lipoproteins and lipoprotein subspecies profile in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 1359–68
Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta 1993; 1165: 335–8
Kleinveld HA, Demacker PNM, De Haan AFJ, et al. Decreased in vitro oxidizability of low-density lipoprotein in hyperchol-esterolaemic patients treated with 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors. Eur J Clin Invest 1993: 23: 289–95
O’Connor P, Cooke T, Feely J. Effects of HMG-CoA reductase inhibitors on lipids and lipoprotein(a) in hypercholesterolaemia. Drug Invest 1992; 4: 227–31
Slunga L, Johnson O, Dahlén GH. Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolaemia with simvastatin. Eur J Clin Pharmacol 1992; 43: 369–73
Thiery J, Armstrong VW, Schleef J, et al. Serum lipoprotein Lp(a) concentrations are not influenced by an HMG CoA reductase inhibitor. Klin Wochenschr 1988; 66: 462–3
Fieseler HG, Armstrong VW, Wieland E, et al. Serum Lp(a) concentrations are unaffected by treatment with the HMG-CoA reductase inhibitor pravastatin: results of a 2-year investigation. Clin Chim Acta 1991; 204: 291–300
Dallongeville J, Fruchart JC, Pfister P, et al. Effect of fluvastatin on plasma apolipoprotein-B-containing particles, including lipoprotein(a). J Intern Med 1994; 236: 95–101
Lagrost L. Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies. Biochim Biophys Acta 1994; 1215: 209–36
Homma Y, Ozawa H, Kobayashi T, et al. Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia. Atherosclerosis 1995; 114: 223–34
Cheung MC, Austin MA, Moulin P, et al. Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia. Atherosclerosis 1993; 102: 107–19
Uusitupa MIJ, Miettinen TA, Happonen P, et al. Lathosterol and other noncholesterol sterols during treatment of hypercholesterolemia with lovastatin alone and with cholestyramine or guar gum. Arterioscler Thromb 1992; 12: 807–13
Vanhanen H, Kesäniemi YA, Miettinen TA. Pravastatin lowers serum cholesterol, cholesterol-precursor sterols, fecal steroids, and cholesterol absorption in man. Metabolism 1992; 41: 588–95
Bertolotti M, Abate N, Loria P, et al. Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7a-hydroxylation rates in vivo. Hepatology 1991; 14: 830–7
Mitchell JC, Logan GM, Stone BG, et al. Effects of lovastatin on biliary lipid secretion and bile acid metabolism in humans. J Lipid Res 1991; 32: 71–8
Goldberg IJ, Holleran S, Ramakrishnan R, et al. Lack of effect of lovastatin therapy on the parameters of whole-body cholesterol metabolism. J Clin Invest 1990; 86: 801–8
Cianflone K, Bilodeau M, Davignon J, et al. Modulation of chylomicron remnant metabolism by an hepatic hydroxy-methylglutaryl coenzyme A reductase inhibitor. Metabolism 1990; 39: 274–80
Arad Y, Ramakrishnan R, Ginsberg HN. Effects of lovastatin therapy on very-low density lipoprotein triglyceride metabolism in subjects with combined hyperlipidemia: evidence for reduced assembly and secretion of triglyceride-rich lipoproteins. Metabolism 1992; 41: 487–93
Hochgraf E, Levy Y, Aviram M, et al. Lovastatin decreases plasma and platelet cholesterol levels and normalizes elevated platelet fluidity and aggregation in hypercholesterolemic patients. Metabolism 1994; 43: 11–7
Johansson J, Mölgaard J, Olsson AG. Plasma high density lipoprotein particle size alteration by simvastatin treatment in patients with hypercholesterolaemia. Atherosclerosis 1991; 91: 175–84
Crook D, Bruce R, Worthington M, et al. Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in type IIa hypercholesterolemia. Cardiovasc Drugs Ther 1992; 6: 633–9
Gaw A, Packard CJ, Murray EF, et al. Effects of simvastatin on ApoB metabolism and LDL subfraction distribution. Arterioscler Thromb 1993; 13: 170–89
Sehayek E, Butbul E, Avner R, et al. Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors. Eur J Clin Invest 1994; 24: 173–8
Vega GL, Krauss RM, Grundy SM. Pravastatin therapy in primary moderate hypercholesterolaemia: changes in metabolism of apolipoprotein B-containing lipoproteins. J Intern Med 1990: 227: 81–94
Franceschini G, Cassinotti M, Vecchio G, et al. Pravastatin effectively lowers LDL cholesterol in familial combined hyperlipidemia without changing LDL subclass pattern. Arterioscler Thromb 1994; 14: 1569–75
Ordovas JM, Lopez-Miranda J, Jimenez-Perez F, et al. Effect of apolipoprotein E and A-IV phenotypes on other low density lipoprotein response to HMG CoA reductase inhibitor therapy. Atherosclerosis 1995: 113: 157–66
Okamoto S, Nakano K, Kosahara K, et al. Effects of pravastatin and ursodeoxycholic acid on cholesterol and bile acid metabolism in patients with cholesterol gallstones. J Gastroenterol 1994; 29: 47–55
Horiuchi I, Ohya T, Tazuma S, et al. Effects of pravastatin (CS-514) on biliary lipid metabolism in patients with hyperlipidemia. Metabolism 1991; 40: 226–30
Jacob BG, Möhrle W, Richter WO, et al. Short-and long-term effects of lovastatin and pravastatin alone and in combination with cholestyramine on serum lipids, lipoproteins and apolipoproteins in primary hypercholesterolaemia. Eur J Clin Pharmacol 1992; 42: 353–8
Illingworth DR, O’Malley JP. The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia. Metabolism 1990; 39: 403–9
Da Col PG, Fonda M, Fisicaro M, et al. Tolerability and efficacy of combination therapy with simvastatin plus gemfibrozil in type IIb refractory familial combined hyperlipidemia. Curr Ther Res 1993: 53: 473–83
Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264: 71–5
Masters BA, Palmoski MJ, Flint OP, et al. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl Coenzyme Areductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol 1995; 131: 163–74
Contermans J, Smit JWA, Bär PR, et al. A comparison of the effects of simvastatin and pravastatin monotherapy on muscle histology and permeability in hypercholesterolaemic patients. Br J Clin Pharmacol 1995; 39: 135–41
Kostis JB, Rosen RC, Wilson AC. Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin in sleep and cognitive performance in patients with hypercholesterolemia. J Clin Pharmacol 1994; 34: 989–96
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. Lancet 1994; 344: 1383–9
Bocan TMA, Mazur MJ, Mueller SB, et al. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis 1994; 111: 127–42
Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995: 15: 678–82
McCarthy PA. New approaches to atherosclerosis: an overview. Med Res Rev 1993: 13: 139–59
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Desager, JP., Horsmans, Y. Clinical Pharmacokinetics of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors. Clin-Pharmacokinet 31, 348–371 (1996). https://doi.org/10.2165/00003088-199631050-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199631050-00003