Abstract
The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions.
Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold.
Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring.
Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.
Similar content being viewed by others
References
Johnson J, Bootman J. Drug-related morbidity and mortality: a cost of illness model. Arch Intern Med 1995; 155: 1949–56
Philips D, Christenfeld N, Glynn L. Increase in US medicationerror deaths between 1983 and 1993. Lancet 1998; 351: 643–4
Berwick D. Reducing errors in medicine. BMJ 1999; 319: 136–7
Classen D, Pestonik S, Evans S, et al. Adverse drug events in hospitalised patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997; 227: 301–6
Bates DW, Spell N, Cullen D, et al. The costs of adverse drug events in hospitalised patients. JAMA 1997; 277: 307–11
European Agency for the Evaluation of Medicinal Products (EMEA). CPMP note for guidance on the investigation of drug interactions: CPMP/EWP/560/95, 1998
Brodie M, Feely J. Adverse drug interactions. In: Feely J, editor. New Drugs. London: BMJ, 1994: 41–55
Nies A. Principles of therapeutics. In: Goodman Gilman A, Rail T, Nies A, et al., editors. Goodman & Gillman’s the pharmacological basis of therapeutics. New York: McGraw Hill, 1991: 62–83
Herman R. Drug interactions and the statins. CMAJ 1999; 161: 1281–6
Moghadasian M. Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci 1999; 65: 1329–37
Stein EA. Extending therapy options in treating lipid disorders: a clinical review of cerivastatin, a novel HMG-CoA reductase inhibitor. Drugs 1998; 56 Suppl. 1: 25–31
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival study (4S). Lancet 1994; 344: 1383–9
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 AFCAPSA/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279: 1615–22
Herd A, Ballantyne C, Farmer J, 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: 278–86
Long-term Intervention with Pravastatin Ischaemic 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: 1349–57
Sacks F, Pfeffer M, Moye L, 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
Shephard J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hpercholesterolaemia. N Engl J Med 1995; 333: 1301–7
Grundy SM, Cleeman JI, Rifkind BM, et al. Cholesterol lowering in the elderly population. Coordinating Committee of the National Cholesterol Education Program. Arch Intern Med 1999; 159: 1670–8
Simes J. Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholestoral concentrations: the LIPID trial follow-up. Lancet 2002; 359: 1379–87
Hebert PR, Gaziano JM, Chan KS, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278: 313–21
Kmietowitz Z. Statins are the new aspirin, Oxford Researchers say [abstract]. BMJ 2001; 323: 1145
Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and Other Societies on Coronary Prevention. Atherosclerosis 1998; 140: 199–270
Miettinen T, Pyorala K, Olsson A, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris. Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997; 96: 4211–8
Wallis E, Ramsay L, Ilaq I, et al. Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population. BMJ 2000; 320: 671–6
Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 2000; 320: 709
Feely J, McGettigan P, Kelly A. Growth in use of statins after trials is not targeted to most appropriate patients. Clin Pharmacol Ther 2000; 67: 438–41
Crouse J, Byington R, Bond M, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol 1995; 75: 455–9
Arntz H-R. Evidence for the benefit of early intervention with pravastatin for secondary prevention of cardiovascular events. Atherosclerosis 1999; 147: S17–21
Charatan F. US spending on prescription drugs rose by 19% in 2000 [abstract]. BMJ 2001; 322: 1198
Pedersen T, Kjekshus J, Berg K, et al. Cholesterol lowering and the use of healthcare resources. Circulation 1996; 93: 1796–802
Goa K, Barradell L, McTavish D. Simvastatin: a reappraisal of its cost effectiveness in dyslipidaemia and coronary heart disease. Pharmacoeconomics 1997; 11: 89–110
Pharoah P, Hollingworth W. Cost effectiveness of lowering cholesterol concentration with statins in patients with and without pre-existing coronary heart disease: life table method applied to health authority population. BMJ 1996; 312: 1443–6
Blum C. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Am J Cardiol 1994; 73: D3–11
Tobert J. Efficacy and long term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62: J28–34
Farmer J, Gotto A. Choosing the right lipid-regulating agent. Drugs 1996; 52: 649–61
Dujovne C, Chremos A, Pool J, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. IV. Additional perspectives on the tolerability of lovastatin. Am J Med 1991; 91 Suppl. 1B: S25–30
Lea A, McTavish D. Atorvastatin: a review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53: 828–47
Maron D, Fazio S, Linton M. Current perspectives on statins. Circulation 2000; 101: 207–13
Bermingham RP, Whitsitt TB, Smart ML, et al. Rhabdomyolysis in a patient receiving the combination of cerivastatin and gemfibrozil. Am J Health Syst Pharm 2000; 57: 461–4
Charatan F. Bayer decides to withdraw cholesterol lowering drug. BMJ 2001; 323: 359
Grundy S. HMG-CoA reductase inhibitors for the treatment of hypercholesterolaemia. N Engl J Med 1988; 319: 24–33
Pederson T, Berg K, Cook T, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1996; 156: 2085–92
Maltz H, Balog D, Cheigh J. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporin. Ann Pharmacother 1999; 33: 1176–9
Bliznakov E, Wilkins D. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): a critical overview. Adv Ther 1998; 15: 218–28
Ucar M, Mjorndal T, Dahlquivist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 2000; 6: 441–57
Anonymous. 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. JAMA 1993; 269: 3015–123
Desager J, Horsmans Y. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet 1996; 31: 348–71
Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors — similarities and differences. Clin Pharmacokinet 1997; 32: 403–25
Bottorff M, Yenkowsky J, Cave D. Use of diagnostic cluster methodology for therapeutic costing and drug surveillance of HMG-CoA reductase-inhibitor therapy. Clin Ther 1999; 21: 218–35
Colley C, Lucas L. Polypharmacy: the cure becomes the disease. J Gen Intern Med 1993; 8: 278–83
Stewart R, Cluff L. A review of medication errors and compliance in ambulant patients. Clin Pharmacol Ther 1972; 13: 463–8
Bergman U, Wiholm B. Drug-related problems causing admission to a medical clinic. Eur J Clin Pharmacol 1981; 20: 193–200
Borortoff M. ‘Fire and forget’ — pharmacological considerations in coronary care. Atherosclerosis 1999; 147: S23–30
Bays H, Dujovne C. Drug interactions of lipid-altering drugs. Drug Saf 1998; 5: 355–71
Stern R, Yang B-B, Horton M, et al. Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin. J Clin Pharmacol 1997; 37: 816–9
Duggan D, Vickers S. Physiological disposition of HMG-CoA-reductase inhibitors. Drug Metab Rev 1990; 22: 333–62
Mevacor (lovastatin): summary of product characteristics. New Jersey (NY): Merck Sharpe & Dohme Limited, 2000
Duggan D, Chen I, Bayne W, et al. The physiological disposition of lovastatin. Drug Metab Dispos 1989; 17: 166–73
Quion J, Jones P. Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet 1994; 27: 94–103
Hsiang B, Zhu Y, Wang Z, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoAreductase inhibitor transporters. J Biol Chem 1999; 274: 37161–8
Singhvi S, Pan H, Morrison R, et al. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol 1990; 29: 239–43
Lipostat (pravastatin): summary of product characteristics. Dublin, Ireland: Bristol-Myers Squibb Limited, 2000
Halstenson C, 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
Haria M, McTavish D. Pravastatin: a reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. Drugs 1997; 53: 299–336
Tsujita Y, Kuroda M, Shimada Y, et al. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidaemic effects on various animal species. Biochim Biophys Acta 1986; 877: 50–60
Amorosa L, Rozovski S, Ananthakrishnan R, et al. Effects of pravastatin on cholesterol metabolism in Watanabe heritable hyperlipidaemic rabbits. Jpn Heart J 1992; 33: 451–63
Koga T, Shimada Y, Kuroda M. 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
Joshi H, Fakes M, Serajuddin A. Differentiation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors by their relative lipophilicity. Pharm Pharmacol Commun 1999; 5: 269–71
Todd P, Goa K. Simvastatin: a review of its pharmacological properties and potential in hypercholesterolaemia. Drugs 1990; 40: 583–607
Vickers S, Duncan C, Chen I, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos 1990; 18: 138–45
Muck W, Ritter W, Ochmann K, et al. Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin. Int J Clin Pharmacol Ther 1997; 35: 255–60
Mazzu A, Lettieri J, Heller A, et al. Ascending multiple dose safety, tolerability and pharmacokinetics of rivastatin in humans [abstract]. Clin Pharmacol Ther 1993; 53: 230
Muck W, Ochmann K, Rohde G, et al. Influence of erythromycin pre- and co-treatment on the single-dose pharmacokinetics of cerivastatin. Eur J Clin Pharmacol 1998; 53: 469–73
Muck W. Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions. Drugs 1998; 56 Suppl. 1: 15–23
Bischoff H, Heller A. Preclinical and clinical pharmacology of cerivastatin. Am J Cardiol 1998; 82: J18–25
Chong P, Seeger J. Atorvastatin calcium: an addition to HMG-CoA reductase inhibitors. Pharmacotherapy 1997; 17: 1157–77
Langtry H, Markham A. Fluvastatin: a review of its use in lipid disorders. Drugs 1999; 57: 583–606
Tse F, Jaffe J, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol 1992; 32: 630–8
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: 410–6
Zocor (simvastatin): summary of product characteristics. Dublin, Ireland: Merck Sharpe & Dohme Limited, 2000
Lescol (fluvastatin): summary of product characteristics. Dublin, Ireland: Novartis Limited, 2000
Lipitor (atorvastatin): summary of product characteristics. Dublin, Ireland: Parke-Davis, 2000
Lipobay (cerivastatin): summary of product characteristics. Dublin, Ireland: Bayer Limited, 2000
Boyd RA, Stern RH, Stewart BH, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 2000; 40: 91–8
Wacher V, Wu C, Benet L. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–34
Kim RB, Wandel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408–14
Christians U, Jacobsen W, Floren L. 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: 1–34
Alsenz J, Steffen H, Alex R. Active apical secretory efflux of the HIV protease inhibitors saquinavir and ritonavir in Caco-2 cell monolayers. Pharm Res 1998; 15: 423–8
Fromm MF, Kim RB, Stein CM, et al. Inhibition of P-glycoproteinmediated drug transport a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 1999; 99: 552–7
Bogman K, Peyer A-K, Torok M, et al. HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br J Pharmacol 2001; 132: 1183–92
Richter W, Jacob B, Schwandt P. Interaction between fibre and lovastatin [letter]. Lancet 1991; 338: 706
Pan H, De Vault A, Swites B. Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolaemia. Clin Pharmacol Ther 1990; 48: 201–7
Nakai A, Nishikata M, Matsuyama K, et al. Drug interaction between simvastatin and cholestyramine in vitro and in vivo. Biol Pharm Bull 2000; 19: 1231–3
Smith H, Jokubaitis L, Troendle A, et al. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens 1993; 6: 375S–82S
Muck W, Ritter W, Frey R, et al. Influence of cholestyramine on the pharmacokinetics of cerivastatin. Int J Clin Pharmacol Ther 1997; 35: 250–4
Pan H, DeVault A, Brescia D, et al. Effect of food on pravastatin pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther Toxicol 1993; 31: 291–4
Deslypere J. Clinical implications of the biopharmaceutical properties of fluvastatin. Am J Cardiol 1994; 73: D12–7
Mazzu A, Lettieri J, Heller A. Pharmacokinetics of cerivastatin administration with and without food in the morning and evening [abstract]. Atherosclerosis 1997; 130: S29
Radulovic L, Cilla D, Posvar E, et al. Effect of food on the bioavailability of atorvastatin, an HMG-CoAreductase inhibitor. J Clin Pharmacol 1995; 35: 990–4
Plosker G, Wagstaff A. Fluvastatin. A review of its pharmacology and use in the management of hypercholesterolaemia. Drugs 1996; 51: 433–59
Baily D, Arnold J, Munoz C, et al. Grapefruit-felodipine interaction: mechanism, predictability, and effect of naringin. Clin Pharmacol Ther 1993; 53: 637–42
Ducharme M, Provenazo R, Dehoorne-Smith M. Trough concentrations of cyclosporin in blood following administration with grapefruit juice. Br J Clin Pharmacol 1993; 36: 457–9
Kupferschmidt H, Ha H, Zeigler W, et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 1995; 58: 383–8
Benton R, Honig P, Zamani K, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarisation on the electrocardiogram. Clin Pharmacol Ther 1996; 59: 383–8
Ameer B, Weintraub R. Drug interactions with grapefruit juice. Clin Pharmacokinet 1997; 33: 103–21
Lilja J, Kivisto K, Neuvonen P. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83
Lilja J, Kivisto K, Neuvonen P. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118–27
Kantola T, Kivisto K, Neuvonen P. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63: 397–402
Neuvonen P, Kantola T, Kivisto K. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41
Kantola T, Kivisto K, Neuvonen P. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65
Neuvonen P, Jalava K. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61
Rogers J, Zhao J, Liu L, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther 1999; 66: 358–66
Lees R, Lees A. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole [letter]. N Engl J Med 1995; 333: 664–5
Norman D, Ilingworth D, Unson J, et al. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin [letter]. N Engl J Med 1988; 318: 46–7
Feely J, O’Connor P. Effects of HMG CoA reductase inhibitors on warfarin binding. Drug Investigation 1991; 3: 315–6
Akhlaghi F, McLachlan A, Keogh A, et al. Effect of simvastatin on cyclosporin unbound fraction and apparent blood clearance in heart transplant recipients. Br J Clin Pharmacol 1997; 44: 537–42
Azie N, Brater D, Becker P, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 369–77
Kivisto K, Kantola T, Neuvonen P. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53
Horsmans Y. Differential metabolism of statins: importance of drug-drug interactions. Eur Heart J 1999; 1 Suppl. T: 7–12
Bottorff M, Hansten P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors — the role of metabolism: monograph for physicians [review]. Arch Intern Med 2000; 160: 2273–80
Nakagawa K, Ishizaki T. Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine. Pharmacol Ther 2000; 86: 1–28
Dressier G, Spence D, Bailey D. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41–57
Transon C, Leeman T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isoenzymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996; 50: 209–15
Bertz R, Granneman G. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32: 210–58
Jacobson W, Kirchner G, Allensleben K, et al. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999; 27: 173–9
Vyas K, Kari P, Wang R, 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 R, Kari P, Lu A, 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
East C, Alivizatos P, Grundy S, et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation [letter]. N Engl J Med 1988; 318: 47–8
Gullestad L, Nordal K, Berg K, et al. Interaction between lovastatin and cyclosporin A after heart and kidney transplantation. Transplant Proc 1999; 31: 2163–5
Tobert J. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation [letter]. N Engl J Med 1988; 318: 48
Olbrict C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporin-treated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62: 311–21
Kobashigawa J, Murphy F, Stevenson L, et al. Low-dose lovastatin safely lowers cholesterol after cardiac transplantation. Circulation 1990; 82: 281–3
Traindl O, Reading S, Franz M, et al. Low-dose lovastatin in hyperlipidemic kidney graft recipients with cyclosporine A. Transplant Proc 1992; 24: 2745–7
Kandus A, Kovac D, Koselj M, et al. Lovastatin treatment of hyperlipidemia in kidney transplant recipients on cyclosporine immunosuppression. Transplant Proc 1994; 26: 2642–3
Grunden J, Fisher K. Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin. Ann Pharmacother 1997; 31: 859–63
Ayanian J, Fuchs C, Stone R. Lovastatin and rhabdomyolysis [letter]. Ann Intern Med 1988; 109: 682–3
Horn M. Coadministration of itraconazole with hypolipidaemic agents may induce rhabdomyolysis in healthy individuals [letter]. Arch Dermatol 1996; 132: 1254
Prueksaritanont T, Bennett M, Tang C, et al. Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. Br J Clin Pharmacol 1999; 47: 291–8
Wallace C, Mueller B. Lovastatin-induced rhabdomyolysis in the absence of concomitant drugs. Ann Pharmacother 1992; 26: 190–2
Regazzi M, 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
Yoshimura N, Oka T, Okamoto M, et al. The effects of pravastatin on hyperlipidaemia in renal transplant recipients. Transplantation 1992; 53: 94–9
Becquemont L, Func-Brentano C, Jaillon P. Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics. Fundam Clin Pharmacol 1999; 13: 232–6
Pan H, Triscan J, De Vault A, et al. Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin. Br J Clin Pharmacol 1991; 31: 655–70
Oo C, Akbari B, Lee S, et al. Effect of orlistat, a novel anti-obesity agent, on the pharmacokinetics and pharmacodynamics of pravastatin in patients with mild hypercholesterolaemia. Clin Drug Invest 1999; 17: 217–33
Alderman C. Possible interaction between nefazodone and pravastatin [abstract]. Ann Pharmacother 1999; 33: 871
Bottorff M. Comment: possible interaction between nefazodone and pravastatin [letter]. Ann Pharmacother 2000; 34: 538–9
Arnadottir M, Eriksson L, Thysell H, et al. Plasma concentration profiles of simvastatin 3-hydroxy-3 methylglutaryl-co-enzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin. Nephron 1993; 65: 410–3
Weise W, Possidente C. Fatal rhabdomyolysis associated with simvastatin in a renal transplant patient. Am J Med 2000; 108: 152–351
Kantola T, Rivisto K, Neuvonen P. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82
Yeo K, Yeo W, Wallis EJ, et al. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. Br J Clin Pharmacol 1999; 48: 610–5
Mousa O, Brater DC, Sunblad KJ, et al. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74
Neuvonen P, Kantola T, Kivisto K. Calcium channel blocker-simvastatin interaction. Reply [letter]. Clin Pharmacol Ther 1999; 65: 583–5
Schmassmann-Suhijar D, Bullingham R, Grasser R, et al. Rhabdomyolysis due to interaction of simvastatin with mibefradil. Lancet 1998; 351: 1929–30
Jacobson R, Wang P, Glueck C. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone [letter]. JAMA 1997; 277: 296
Gilad R, Lampi Y Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22: 295–7
Segaert M, De Soete C, Vandewiele I, et al. Drug-interaction-inducedrhabdomyolysis. Nephrol Dial Transplant 1996; 11: 1846–7
Mogyorosi A, Bradley B, Schubert M. Rhabdomyolysis attributed to HMG-CoA-reductase inhibitor-warfarin interaction [abstract]. Am J Kidney Dis 1999; 33: A36
Mogyorosi A, Bradley B, Showalter A, et al. Rhabdomyolysis and acute renal failure due to combination therapy with simvastatin and warfarin. J Intern Med 1999; 246: 599–602
Gruer P, Vega J, Mercuri M, et al. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999; 84: 811–5
Murphy M, Dominiczak M. Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med 1999; 75: 260–359
von Rosenstiel N, Adam D. Macrolide antibacterial — drug interactions of clinical significance. Drug Saf 1995; 13: 105–22
Mazzu A, Stein EA, Kelly E, et al. Minor alterations in cerivastatin pharmacokinetics by erythromycin and itraconazole. Pharmacotherapy 1999; 19: 480–1
Kantola T, Kivisto K, Neuvonen P. Effect of itraconazole on cerivastatin pharmacokinetics. Eur J Clin Pharmacol 1999; 54: 851–5
Muck W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65: 251–61
Kadmon M, Klunemann C, Bohme M, et al. Inhibition by cyclosporin A of adenosine triphosphate-dependent transport from the hepatocyte into bile. Gastroenterology 1993; 104: 1507–14
Stapf V, Thalhammer T, Huber-Huber R, et al. Inhibition of rhodamine 123 secretion by cyclosporin A as a model of P-glycoprotein mediated transport in liver. Anticancer Res 1994; 14: 581–6
Tuffs A. Bayer faces potential fine over cholesterol lowering drug [abstract]. BMJ 2001; 323: 415a
Siedlik P, Olson S, Yang B-B, et al. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39: 501–4
Wenisch C, Krause R, Fladerer P, et al. Acute rhabdomyolysis after atorvastatin and fusidic acid therapy [letter]. Am J Med 2000; 109: 78
Transon C, Leeman T, Dayer P. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (±)-fluvastatin. Clin Pharmacol Ther 1995; 58: 412–7
Cupp M, Tracey T. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998; 57: 107–16
Appel S, Dingemanse J. Pharmacokinetic and pharmacodynamic interactions of fluvastatin and their therapeutic implications. Rev Contemp Pharmacother 1996; 7: 167–82
Jokubaitis L. Updated clinical safety experience with fluvastatin. Am J Cardiol 1994; 73: D18–24
Olsson A, Pears J, McKellar J, et al. ZD4522 — a new HMG-CoA reductase inhibitor — causes rapid and profound reductions in plasma LDL-C levels in patients with primary hypercholesterolaemia [abstract]. Atherosclerosis 2000; 151: 39
Buckett L, Ballard P, Davidson R, et al. Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non-hepatic cells [abstract]. Atherosclerosis 2000; 151: 41
McCormick A, McKillop D, Batters C, et al. ZD4522-An HMGCo-A reductuse inhibitor free of metabolically mediated drug interactions: metabolic studies in human in vitro systems. Presented at the 29th Annual Meeting of the American College of Clinical Pharmacology; 2000 Sept 17–19; Chicago (IL)
Martin P, Dane A, Schneck D, et al. Disposition of new HMG-CoA reductase inhibitor ZD4522 following dosing in heallhy subjects. Presented at the 29th Annual Meeting of the American College of Clinical Pharmacology; 2000 Sept 17–19; Chicago (IL)
Ahmad S. Lovastatin-warfarin interaction [letter]. Arch Intern Med 1990; 150: 2407
Trenque T, Choisy H, Germain M-L. Pravastatin: possible interaction with oral anticoagulant? [abstract]. BMJ 1996; 312: 886
Grau E, Perella M, Pastor E. Simvastatin-oral anticoagulant interaction. Lancet 1996; 347: 405–6
Rise I. Bilateral subdural haematoma caused by simvastatin during warfarin treatment [letter]. Acta Neurol Scand 1997; 96: 339
Lin J, Ito M, Stolly S, et al. The effect of converting from pravastatin to simvastatin on the pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39: 86–90
Stern R, Abel R, Gibson G, et al. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol 1997; 37: 1062–4
Trilli L, Kelley C, Aspinall S, et al. Potential interaction between warfarin and fluvastatin. Ann Pharmacother 1996; 30: 1399–402
Kline S, Harrell C. Potential warfarin-fluvastatin interaction [letter]. Ann Pharmacother 1997; 31: 790
Schall R, Mueller F, Hundt H, et al. No pharmacokinetic or pharmacodynamic interaction between rivastatin and warfarin. J Clin Pharmacol 1995; 35: 306–13
Weber P, Lettieri J, Kaiser L, et al. Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolaemic volunteers. Clin Ther 1999; 21: 1563–75
Lettieri J, Krol G, Mazzu A, et al. Lack of pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin [abstract]. Atherosclerosis 2000; 130: S29
Malinoski J. Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. Am J Health Syst Pharm 1998; 55: 2253–67
Stern R, Smithers J, Olson S. Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine. J Clin Pharmacol 1998; 38: 753–7
Yang B-B, Hounslow N, Sedman A, et al. Effects of atorvastatin, an HMG-CoA reductase inhibitor, on hepatic oxidative metabolism of antipyrine. J Clin Pharmacol 1996; 36: 356–60
Yang B-B, Smithers J, Abel R, et al. Atorvastatin pharmacokinetic interactions with other CYP3A4 substrates: erythromycin and ethinyl estradiol [abstract]. Pharm Res 1996; 13: S437
Salonen J, Malin R, Tuomainen T-P, et al. Polymorphism in high density lipoprotein paraoxonase gene and risk of acute myocardial infarction in men: prospective nested case-control study. BMJ 1999; 319: 487–9
Nordin C, Dahl M, Erikson M, et al. Is the cholesterol-lowering effect of simvastatin influenced by CYP2D6 polymorphism? Lancet 1997; 350: 29–30
Jukema J, Bruschke A, van Boven A, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528–40
Sacks F, Gibson C, Rosner B, et al. The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypercholesterolaemic therapy on coronary atherosclerosis in angiographic trials. Am J Cardiol 1995; 76: C78–85
Stenestrand UM, Wallentin LMP, for the Swedish Registerof Cardiac Intensive Care, et al. Early slatin treatment following acute myocardial infarction and 1-year survival. JAMA 2001; 285: 430–6
Vaughan C, Murphy M, Buckley B. Statins do more than just lower cholesterol. Lancet 1996; 348: 1079–82
Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolaemia. Circulation 1994; 85: 2419–524
Treasure C, Klein J, Weintraub W, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332: 481–7
Straznicky N, Howes L, Lam W, et al. Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolaemia and systemic hypertension. Am J Cardiol 1995; 75: 582–6
Aengevaeren W. Beyond lipids — the role of the endothelium on coronary artery disease. Atherosclerosis 1999; 147: S11–6
Feron OP, Dessy CP, Desager J-PP, et al. Hydroxymethylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 2001; 103: 113–8
Rosensen R, Tangney C. Antithrombotic properties of statins. JAMA 1998; 279: 1643–50
Mayer J, Eller T, Brauer P, et al. Effects of long-term treatment with lovastatin on the clotting system and blood platelets. Ann Haematol 1992; 64: 196–201
Lacoste L, Lam L, Hung J, et al. Hypercholesterolaemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995; 92: 3172–7
Notarbartolo A, Davi G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolaemia. Effects of pravastatin. Arterioscler Thromb Vasc Biol 1995; 15: 247–51
Buemi M, Allegra A, Corica F, et al. Effect of fluvastatin on proteinuria in patients with immunoglobulin A nephropathy. Clin Pharmacol Ther 2000; 67: 427–31
Tonolo G, Ciccarese M, Brizzi P, et al. Reduction of albumin excretion rate in normotensive microalbuminuric type 2 diabetic patients during long term simvastatin treatment. Diabetes Care 1997; 20: 1891–5
Grandgaliano G, Biswas P, Choudhury G, et al. Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Kidney Int 1993; 44: 503–8
Buemi M, Allegra A, Senatore M, et al. Pro-apoptopic effect of fluvastatin on human muscle cells. Eur J Pharmacol 1999; 370: 201–3
Cummings S, Bauer D. Do statins prevent both cardiovascular disease and fracture? JAMA 2000; 283: 3255–7
Rabelink A, Hene R, Erkelens D, et al. Partial remission of nephrotic syndrome in patients on long-term simvastatin. Lancet 1990; 335: 1045–6
Wang P, Soloman D, Mogun H, et al. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 2000; 283: 3211–6
Meier C, Schlienger R, Kraenzlin M, et al. HMG-CoA reductase inhibitors and the risk of fractures. JAMA 2000; 283: 3205–10
Su SF, Hsiao CL, Chu CW, et al. Effects of pravastatin on left ventricular mass in patients with hyperlipidemia and essential hypertension. Am J Cardiol 2000; 86: 514–8
Pepys MB. The renaissance of C reactive protein: it may be a marker not only of acute illness but also of future cardiovascular disease [editorial]. BMJ 2001; 322: 4–5
Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100: 230–5
Packard C, O’Reilly D, Caslake M, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med 2000; 343: 1148–55
Kobashigawa J, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333: 621–7
Weissberg P. Mechanisms modifying atherosclerotic disease-from lipids to vascular biology. Atherosclerosis 1999; 147: S3–10
Rubins H, Robins S, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341: 410–8
Frick M, Elo O, Haapa K, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidaemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237–45
Pierce L, Wysowski D, Gross T. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264: 71–5
Van Puijenbroek E, Du-Buf-Vereijken P, Spooren PVDJ. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med 1996; 240: 403–4
Wiklund O, Bergman M, Bondjers G, et al. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolaemia. Am J Med 1993; 94: 13–20
Miller D, Spence J. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 1998; 34: 155–62
Garnett W. Interactions with hydroxymethyl-CoA reductase inhibitors. Am J Health Syst Pharm 1995; 52: 1639–45
Rosensen R, Frauenheim W. Safety of combined pravastatingemfibrozil therapy. Am J Cardiol 1995; 74: 499–500
Pan WJ, Gustavson LE, Achari R, et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol 2000; 40: 316–23
Illingworth DR, O’Malley K. The hypolipidaemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia. Metabolism 2001; 1990: 403–9
Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998; 81: 368–9
Pogson G, Kindred L, Carper B. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy [letter]. Am J Cardiol 1999; 83: 1146
Alexandridis G, Pappas GA, Elisaf MS. Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil [letter]. Am J Med 2000; 109: 261–2
Ozdemir O, Boran M, Gokce V, et al. A case with severe rhabdomyolysis and renal failure associated with cerivastatingemfibrozil combination therapy — a case report. Angiology 2000; 51: 695–7
Illingworth DR, Bacon S. Treatment of heterozygous familial hypercholesterolaemia with lipid-lowering drugs. Arteriosclerosis 1989; 9: 1121–34
Hoogerbrugge N, Mol M, Van Dormaal J, et al. The efficacy and safety of pravastatin, compared to and in combination with bile acid binding resins, in familial hypercholesterolaemia. J Intern Med 1990; 228: 261–6
Farmer J, Gotto A. Antihyperlipidaemic agents: drug interactions of clinical significance. Drug Saf 1994; 11: 301–9
Reaven P, Witztum J. Lovastatin, nicotinic acid, and rhabdomyolysis [letter]. Ann Intern Med 1988; 109: 597–8
Jacobson T. Fluvastatin with and without niacin for hypercholesterolaemia. Am J Cardiol 1994; 74: 149–54
Stein EA, Davidson M, Dujovne C, et al. Efficacy and safety of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidaemia: a prospective trial. J Cardiovasc Pharmacol Ther 1996; 1: 107–16
Vacek JL, Dittmeier G, Chiarelli T, et al. Comparison of lovastatin (20 mg) and nicotinic acid (1.2 g) with either drug alone for type II hyperlipoproteinemia. Am J Cardiol 1995; 76: 182–4
Gardner SF, Schneider EF, Granberry MC, et al. Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin. Pharmacotherapy 1996; 16: 419–23
Kobashigawa J, Kasiske B. Hyperlipidaemia in solid organ transplantation. Transplantation 1997; 63: 331–8
Kirk J, Dupuis R. Approaches to the treatment of hyperlipidaemia in the solid organ transplant recipient. Ann Pharmacother 1995; 29: 879–91
Knopp R. Drug treatment of lipid disorders. N Engl J Med 1999; 341: 498–511
Corpier C, Jones P, Suki W, et al. Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. JAMA 1988; 260: 239–41
Goldberg R, Roth D. A preliminary report of the safety and efficacy of fluvastatin for hypercholesterolaemia in renal transplant patients receiving cyclosporine. Am J Cardiol 1995; 76: A107–9
Southworth M, Mauro V. The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients. Ann Pharmacother 1997; 31: 489–91
Capone D, Stanziale P, Gentile A, et al. Effects of simvastatin and pravastatin on hyperlipidaemia and cyclosporin blood levels in renal transplant recipients. Am J Nephrol 1999; 19: 411–5
Barbir M, Rose S, Kushwaha S, et al. Low-dose simvastatin for the treatment of hypercholesterolaemia in recipients of cardiac transplantation. Int J Cardiol 1991; 33: 241–6
Rodriguez J, Crespo-Leiro M, Paniangua M, et al. Rhabdomyolysis in heart transplant patients on HMG-Co-A reductase inhibitors and cyclosporine. Transplant Proc 1999; 31: 2522–3
Keogh A, Macdonald P, Kaan A, et al. Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation. J Heart Lung Transplant 2000; 19: 529–37
Li P, Mak T, Wang A, et al. The interaction of fluvastatin and cyclosporin A in renal transplant patients. Int J Clin Pharmacol Ther 1995; 33: 246–8
Hadjigavriel M, Kyriakides G. Fluvastatin in renal transplantation [abstract]. Transplant Proc 1997; 29: 3050
Li P, Mak T, Chan T, et al. Effect of fluvastatin on lipoprotein profiles in treating renal transplant recipients with dyslipoproteinaemia. Transplantation 1995; 60: 652–6
Acknowledgements
John Feely has participated in clinical trials with pravastatin, simvastatin, atorvastatin and rosuvastatin. David Williams has participated in clinical trials with atorvastatin and rosuvastatin. We would like to thank Ms Orla Sheehan for her assistance in the preparation of this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Williams, D., Feely, J. Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors. Clin Pharmacokinet 41, 343–370 (2002). https://doi.org/10.2165/00003088-200241050-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200241050-00003