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CMAJ • November 16, 1999; 161 (10)
© 1999 Canadian Medical Association or its licensors

Education
Éducation

Drug interactions and the statins

Robert J. Herman, MD

From the Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Sask.

Abstract

Drug interactions commonly occur in patients receiving treatment with multiple medications. Most interactions remain unrecognized because drugs, in general, have a wide margin of safety or because the extent of change in drug levels is small when compared with the variation normally seen in clinical therapy. All drug interactions have a pharmacokinetic or pharmacodynamic basis and are predictable given an understanding of the pharmacology of the drugs involved. Drugs most liable to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose-response curves; those having high first-pass metabolism or those with a single, inhibitable route of elimination. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interactions that can occur with hydroxymethylglutaryl - coenzyme A (HMG-CoA) reductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs.

Background

All important drug interactions, with the possible exception of idiosyncratic or allergic reactions, have a pharmacokinetic or pharmacodynamic basis, or both.1,2 Pharmacokinetic interactions refer to those where drugs or other factors cause an alteration in the concentration of unbound drug acting on the tissues. They include interactions that may lead to changes in drug absorption, drug distribution (either through binding to plasma proteins or, more importantly, binding and uptake into tissues) and drug elimination. Pharmacodynamic interactions refer to those where changes occur in tissue sensitivity or response to the same unbound drug concentrations.

The consequences of a drug interaction depend upon patient-related as well as drug-related factors (Fig. 1).3 These include the magnitude and direction of the concentration or effect changes, as well as the steepness and separation of the dose-response of the drug's intended (therapeutic) and unintended (adverse) pharmacologic actions.1 Large changes in the concentration or tissue response to a drug possessing a flat dose-response relation or low intrinsic toxicity may be of little clinical importance. Alternatively, small changes in the concentration of potent or highly toxic drugs can be disastrous. Individual susceptibility to adverse drug effects because of health- (e.g., age, pregnancy) and disease-related factors (e.g., renal, hepatic, CNS) should also be considered. As well, the body may minimize a drug's effect through offsetting changes in tissue sensitivity, by up-regulation or down-regulation of receptor numbers or by changes in receptor-effector coupling, or both.4 What might produce minimal impairment on one occasion could be incapacitating on another occasion or in a less tolerant individual.



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  		Fig. 1: Factors influencing drug interactions. (Adapted from Hansten).3

 

Interactions between drugs binding to the same sites on plasma proteins are rarely associated with changes in drug response.1,2 The reason for this is that most of the drug exists in the body in tissue stores, mainly in muscle and fat, not in the circulation. Thus, even large decreases in the amount of drug bound to plasma proteins is effectively buffered by a greater distribution in peripheral tissues with little or no change in unbound concentrations. The one exception occurs with drugs possessing small distribution volumes, like warfarin, where binding interactions confined largely to the circulation produce large changes in unbound concentrations and drug effects. What is important to remember is that laboratories usually report total drug concentrations and not unbound drug concentrations. Therefore, target ranges of clinically monitored drugs should be adjusted downwards in the presence of a binding interaction, normally with no change in dosage. Similar considerations apply if the levels of albumin or other binding proteins are not within the expected range.

In contrast, displacement from tissue-based binding sites or the inhibition of carrier-mediated uptake into tissues can produce large changes in unbound drug concentrations.2 Drugs and their metabolites move out of tissues as readily as they move in, and muscle and fat often contain large body stores, particularly following multiple dosing. The factors causing redistribution from tissues into the circulation are not well understood, although evidence suggests that this occurs commonly with lipophilic drugs that have large distribution volumes.5 Examples of clinically relevant interactions involving the inhibition of drug distribution and transport include the 2- to 3-fold elevations in digoxin serum concentrations following the concomitant administration of quinidine or verapamil.6

The inhibition or induction of hepatic drug metabolism is a major source of variability in drug response and is the basis of many adverse drug interactions.7 Paramount to an understanding of this is a consideration of the role of the liver in the overall elimination of the drug. Most drugs are removed from the body through multiple competing pathways of renal and hepatic excretion. If one or several of these become blocked because of disease or the action of another drug, clearance will diminish, dependent upon the relative contribution of the affected pathway(s) to the total elimination of the drug.8 If this occurs, steady-state concentrations and, correspondingly, drug or adverse effects rise. However, these in turn drive elimination through other pathways as long as they are unencumbered. Therefore, drugs that have few or minor alternative pathways are particularly prone to large concentration increases when elimination is impaired.

First-pass metabolism by the gut and liver is another important consideration. If a drug has low oral availability due to high presystemic elimination, there may be large increases in the amount of drug getting into the body if metabolism is inhibited. Where the parent drug is inactive and the pathway normally results in the formation of an active metabolite, drug response may diminish rather than increase when metabolism is inhibited.9 Conversely, response may be unchanged if both parent and metabolites are active - increases in the concentration of the parent offset by decreases in the metabolites.9

The mechanism of interaction is also an important factor; an interacting drug may not be a known inhibitor but merely a substrate for the same metabolic pathway and thereby produce only minor dose-dependent competition at the active enzyme site.10 In this case, the affinity of the substrate for the enzyme and the unbound concentration and half-life of the inhibiting drug are important determinants of the extent and time course of the interaction. Alternatively, inhibition may be noncompetitive or uncompetitive, wherein the effect is likely to be more complete and long lasting, requiring resynthesis of new enzyme before it can be overcome.10

The cytochrome P450 superfamily

Hepatic metabolism is served by a superfamily of oxygenases known as the cytochrome P450s. The purpose of these enzymes is to add a functional group to a drug, an environmental chemical or an endogenous molecule and, in so doing, increase either its polarity and excretion from the body or its interaction with similar enzymes. The most distinguishing characteristic of the cytochrome P450 family is its great diversity; members have a broad and overlapping substrate specificity and an ability to interact with almost any chemical species. The superfamily, referred to as the CYP enzymes, is subdivided according to the degree of homology in amino acid sequences. CYP enzymes possessing more than 40% homology are grouped together into families, which are designated by an Arabic numeral (e.g., the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (e.g., CYP2C and CYP2D subfamilies); members of each subfamily have more than 55% homology with one another. Finally, individual members are given an additional number (e.g., CYP3A4) to identify a specific enzyme pathway. Over 70 CYP families have been identified to date, of which 14 are known to occur in all mammals.11 Of the 26 mammalian subfamilies, the CYP2C, CYP2D and CYP3A subfamilies are involved in the metabolism of most clinically relevant drugs. Important substrates, inducers and inhibitors of the major CYP enzymes are listed in Table 1.


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  		Table 1: Inducers and inhibitors of major CYP enzymes

 

The CYP2C subfamily comprises about 20% of all of the cytochrome P450s in the liver.12 At least 6 different CYP2C isozymes have been characterized, each having greater than 80% homology with distinct but overlapping substrate specificity. Prostaglandins and sex steroids are important endogenous substrates of the CYP2C subfamily. The most abundant enzyme in this subfamily, CYP2C9, is responsible for the breakdown of a number of drugs including ASA and many of the nonsteroidal anti-inflammatory drugs, sulfonamides, phenytoin and S-warfarin (the more active enantiomer of warfarin). CYP2C19 is involved in the metabolism of diazepam, omeprazole and the tricyclic antidepressants. Both CYP2C9 and CYP2C19 are polymorphic, meaning the expression of these enzymes is under strong genetic influence and some individuals have markedly deficient activities. Indeed, 3% of white people and 20% of all those of Japanese descent lack CYP2C19 and are unable to metabolize diazepam and omeprazole by the usual pathways.13,14 However, since many of the enzymes in this family have overlapping substrate specificities, it is unusual to see excessive or adverse drug effects even in people completely deficient in CYP2C19.15 Serious interactions occur predominantly with drugs that have a low therapeutic index such as warfarin or phenytoin.10

CYP2D6 accounts for only 4% of hepatic CYP enzymes,12 but is more unique in its metabolic profile. Important substrates for this enzyme include tricyclic antidepressants, selective serotonin reuptake inhibitors, neuroleptics, opioid analgesics and several of the ß-adrenergic blockers. Seven to 10% of white people and 3% of black and oriental people are known to be deficient in the CYP2D6 enzyme, the so-called sparteine-debrisequine, poor metabolizer polymorph.13,14 These individuals show great variability in clinical response (up to 1000-fold) and commonly have adverse effects to standard doses of drugs metabolized by this enzyme. Also, they are unable to convert codeine, oxycodone and hydrocodone to their active metabolites16 and thereby derive little or no analgesic benefit from oral morphine analogues. Levels of CYP2D6 are not affected by age, sex or smoking status.17 Inhibitors are quinidine, ketoconazole and most antidepressants and neuroleptics, and there are no known inducers of this enzyme.

The CYP3A subfamily, like CYP2D6, is involved in the metabolism of a large number drugs and other chemicals and is involved in many drug-drug and drug-food interactions. It is the most abundant of all of the P450s in the human liver (25%-28%, but sometimes as high as 70%) and is widely expressed throughout the gastrointestinal tract, kidneys and lungs.12 More than 150 drugs are known substrates of CYP3A4, the major CYP3A isozyme, including many of the opiate analgesics, steroids, antiarrhythmic agents, tricyclic antidepressants, calcium-channel blockers and macrolide antibiotics. Although several substrates show age-dependent reductions in elimination, the enzyme itself does not appear to be altered.18 Also, sex-related effects are small and probably not important. Ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, fluvoxamine, fluoxetine, nefazodone, cyclosporine and dihydroxybergamottin and various substances found in grapefruit juice, green tea and other foods are potent inhibitors of CYP3A4 and are known to be responsible for many drug interactions.10,15 Terfenadine, astemizole, cisapride, cyclosporine and many of the hydroxymethylglutaryl - coenzyme A (HMG-CoA) reductase inhibitors are potentially toxic drugs or drugs susceptible to large changes in concentration following enzyme inhibition and, therefore, are candidates for serious interactions with other substrates of CYP3A4.10 These interactions can have serious clinical consequences.

Interactions with HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitors (statins) are associated with 2 uncommon but important side effects, namely asymptomatic elevation in liver enzymes and skeletal muscle abnormalities, which can range from benign myalgias to myopathy (10-fold elevation in creatine kinase with muscle pain or weakness) and life-threatening rhabdomyolysis.19,20 The incidence of myopathy in patients taking statins alone is estimated to be 0.1%-0.2%,20,21 and rhabdomyolysis is exceedingly rare. Evidence suggests that myopathy is a direct consequence of HMG-CoA reductase inhibition22,23 and is dose-dependent.24-27 Myopathy is most likely to occur when statins are administered with other drugs or chemicals that are themselves myotoxic or that elevate the concentrations of the statin to the toxic range. Indeed, the incidence of muscle disorders increases over 10-fold when statins are given with gemfibrozil,20,28-31 niacin,20,32 erythromycin,33 itraconazole,34,35 cyclosporine,20,36,37 and diltiazem38 among others.

Six statins are currently marketed for the treatment of dyslipidemia in North America. Lovastatin, simvastatin, atorvastatin and cerivastatin are all substrates of CYP3A439-41 and would be subject to marked inhibition of metabolism by azole antifungal agents, macrolide antibiotics, selective serotonin reuptake inhibitors, cyclosporine, diltiazem and grapefruit juice. Fluvastatin is metabolized by CYP2C9; it would not be affected by these substrates, but rather would have a different spectrum of interactions,32,42 perhaps less clinically relevant because of the overlap between CYP2C isozymes. Pravastatin is not significantly metabolized by CYP and would be comparatively devoid of these effects.43,44 Lovastatin, simvastatin and atorvastatin are all extensively metabolized on first-pass through the liver39,40,45 with resultant low oral availability (5%-10%), whereas cerivastatin has an intermediate availability of around 60%.46 Moreover, the active CYP3A metabolites of atorvastatin and cerivastatin contribute in large measure to their overall clinical activity.40,46 Thus, inhibition of firstpass metabolism of lovastatin or simvastatin could result in 10-20 fold elevations (oral availability increasing from 5% to 100%) in steady-state concentrations with a marked liability to drug toxicity. Inhibition of metabolism of atorvastatin and cerivastatin, on the other hand, is likely to produce a balanced inhibition with small changes in the total active drug concentration within the normal dosing range. Indeed, pharmacokinetic interactions of these types have been confirmed recently for each of the marketed statins.47-53

A MEDLINE review of all interactions involving a statin and any other drug between 1984 and 1999 revealed 1 case report of rhabdomyolysis in a patient receiving pravastatin and fenofibrate, but 27 cases of rhabdomyolysis in patients on simvastatin combined with either gemfibrozil, nefazodone, cyclosporine, itraconazole or mibefradil and 37 cases in those on lovastatin plus gemfibrozil, niacin, cyclosporine, itraconazole or erythromycin (references available on request). There are numerous other reports documenting lesser degrees of myopathy, myalgia and asymptomatic elevations in creatine kinase showing the same pattern of predilection for lovastatin and simvastatin. However, the mere potential for a drug interaction to occur, even its citation in the literature, provides little indication of the true incidence of adverse outcomes in routine clinical use. Monotherapy with lovastatin, pravastatin and simvastatin has a proven record of safety and efficacy in large clinical trials.21,54,55 Moreover, there are numerous reports in the recent literature documenting the safe use of low dose statin-cyclosporine and statin-fibrate combinations in high-risk patients or patients with complex dyslipidemias56,57 (other references available on request). Indeed, patients who experienced serious toxicity often received other drugs, in addition to the interacting drug cited, that competed with the statin through CYP3A4.

Finally, the interaction of the statins with the fibric acid lipid-lowering agents like gemfibrozil and fenofibrate is thought to have a pharmacodynamic rather than a pharmacokinetic basis. Although rhabdomyolysis has been reported most frequently with lovastatin-fibrate combinations, there have also been cases reported with each of the other marketed statins, except possibly cerivastatin. Studies have not found any fibrate-dependent alterations in statin concentrations, however.28,58 Moreover, statin-induced myopathy is seen with hypothyroidism59-61 or congenital or acquired myopathic conditions.62,63 This drug-disease interaction likely represents a statin-related functional mitochondrial deficit in addition to an inherent tendency toward muscular disease.

Summary

Drug interactions commonly occur in patients taking multiple medications. Although there may be some differences in the potential for statin preparations to be involved in serious adverse drug reactions, in general, they have a proven record of safety and efficacy in large clinical studies. Nonetheless, concern is warranted when statins, particularly lovastatin and simvastatin, are used in multidrug regimens because of dose-dependent toxicity and their propensity toward marked elevations in concentration if taken with drugs that inhibit first-pass metabolism.

Competing interests: Dr. Herman received speaker fees from Bristol-Myers Squibb.

Acknowledgments

A society of physicians who hold positions in the management of health resources or have an interest in the management of health resources.

Annual Meeting; Sheraton Centre, Toronto; Feb. 26-27, 2000

For information contact: Dr. Chris Carruthers; c/o CSPE; 3540 Paul Anka Dr.; Ottawa ON K1V 9K8; email: ccmd{at}home.com; Web site: www.cma.ca/cspe

Footnotes

This article has been peer reviewed.

Reprint requests to: Dr. Robert J. Herman, Department of Pharmacology, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd., Saskatoon SK S7N 5E5; fax 306 966-6220.

This work was supported by an educational grant from Bristol-Myers Squibb. Bristol-Myers Squibb had no control over the content of this manuscript.


References

  1. Nies AS, Spielberg SP. Principles of therapeutics. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 43-62.
  2. Roland M, Tozer TN. Interacting drugs. In: Roland M, Tozer TN, editors. Clinical pharmacokinetics. 2nd ed. Philadelphia: Lea and Febiger; 1989. p. 255-75.
  3. Hansten PD. Understanding drug-drug interactions. Science & Medicine 1998;5(1):16-25.
  4. Ross EM. Mechanisms of drug action and the relationship between drug concentration and effect. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 29-42.
  5. Pounder DJ, Hartley AK, Watmough PJ. Postmortem redistribution and degradation of dothiepin. Human case studies and an animal model. Am J Forensic Med Pathol 1994;15:231-5.[Medline]
  6. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 1999;99:552-7.[Abstract/Free Full Text]
  7. Roland M, Tozer TN. Variability. In: Roland M, Tozer TN, editors. Clinical pharmacokinetics. 2nd ed. Philadelphia: Lea and Febiger; 1989. p. 197-212.
  8. Herman RJ, Szakacs CBN, Verbeeck RK. Analysis of polymorphic variation in drug metabolism: II. Effects of data transformation on the sensitivity and specificity of modal detection. Clin Invest Med 1994;17:290-6.[Medline]
  9. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997;32:210-58.[Medline]
  10. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;18:84-112.[Medline]
  11. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996;6:1-42.[Medline]
  12. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev 1997;29:413-580.[Medline]
  13. Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P450 - structure, mechanism and biochemistry. 2nd ed. New York: Plenum Press; 1995. p. 473-535.
  14. Spatzeneger M, Jaeger W. Hepatic P450 in drug metabolism. Drug Metab Rev 1995;27:397-417.[Medline]
  15. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998;57:107-16.[Medline]
  16. Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine o-demethylation co-segregates with polymorphic debrisequine hydroxylation. Br J Clin Pharmacol 1989;28:639-45.[Medline]
  17. Ozdemir V, Fourie J, Busto U, Naranjo CA. Pharmacokinetic changes in the elderly. Do they contribute to drug abuse and dependence? Clin Pharmacokinet 1996;31:372-85.[Medline]
  18. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992;44:275-83.[Medline]
  19. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988;319:24-33.[Medline]
  20. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988;62:28J-34J.
  21. Pedersen TR, Berg K, Cook TJ, Faergeman O, Haghfelt T, Kjekshus J, 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.[Abstract/Free Full Text]
  22. Hrab RV, Hartman HA, Cox RH Jr. Prevention of fluvastatin-induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation. Teratology 1994;50:19-26.[Medline]
  23. Flint OP, Masters BA, Gregg RE, Durham SK. HMG-CoA reductase inhibitor-induced myotoxicity: pravastatin and lovastatin inhibit the geranylgeranylation of low-molecular-weight proteins in neonatal rat muscle culture. Toxicol Appl Pharmacol 1997;145:99-110.[Medline]
  24. Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol 1995;27:2397-402.[Medline]
  25. Smith PF, Eydelloth RS, Grossman SJ, Stubbs RJ, Schwartz MS, Germershausen JI, et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 1991;257:1225-35.[Abstract/Free Full Text]
  26. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH, et al. The efficacy and 6-week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997;79:38-42.[Medline]
  27. Nakai A, Nishikata M, Uchida T, Ichikawa M, Matsuyama K. Enhanced myopathy following administration of hypolipidemic agents under urethane anesthesia. Biol Pharm Bull 1997;20:104-6.[Medline]
  28. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990;264:71-5.[Abstract/Free Full Text]
  29. Abdul-Ghaffar NU, el-Sonbaty MR. Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy. J Gastroenterol 1995;21:340-1.
  30. Van Puijenbroek EP, Du Buf-Vereijken PWG, Spooren PFMJ, van Doormaal JJ. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med 1996;240:403-4.[Medline]
  31. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. South Med J 1997;90:546-7.[Medline]
  32. Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995;52:1639-45.
  33. Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med 1991;154:213-5.[Medline]
  34. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995;333:664-5.[Free Full Text]
  35. Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals [letter]. Arch Dermatol 1996;132:1254.
  36. Meier C, Stey C, Brack T, Maggiorini M, Risti B, Krahenbuhl S. Rhabdomyolysis in patients treated with simvastatin/ciclosporin: role of the hepatic P450 enzyme. Schweiz Med Wochenschr 1995;125:27-8.
  37. Barclay P, O'Connell P. Clarithromycin drug interactions complicating cyclosporine and simvastatin therapy [abstract]. Austral J Hosp Pharm 1996;26:180.
  38. Ahmad S. Diltiazem myopathy [letter]. Am Heart J 1993;126:1494-5.
  39. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinetics 1997;32:403-25.[Medline]
  40. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidemias. Drugs 1997;53:828-47.[Medline]
  41. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, et al. Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 enzymes involved. Drug Metab Dispos 1997;25:321-31.[Abstract/Free Full Text]
  42. Transon C, Leemann T, Vogt N, Dayer P. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther 1995;58:412-7.[Medline]
  43. Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth I, et al. Comparison of cytochrome P450-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.[Abstract/Free Full Text]
  44. Kocarek TA, Reddy AB. Regulation of cytochrome P450 expression by inhibitors of hydroxymethylglutaryl-coenzyme A reductase in primary cultured rat hepatocytes and in rat liver. Drug Metab Dispos 1996;24:1197-204.[Abstract]
  45. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993;24:195-202.[Medline]
  46. Muck W, Ritter W, Ochmann K, Unger S, Ahr G, Wingender W, et al. Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin. Int J Clin Pharmacol Ther 1997;35:255-60.[Medline]
  47. Azie E, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998;64:369-77.[Medline]
  48. Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996;60:54-61.[Medline]
  49. Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998;46:49-53.[Medline]
  50. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998;63:332-41.[Medline]
  51. Neuvonen PJ, Kantola T, Kivisto KT. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998;64:58-65.[Medline]
  52. Yang BB, Siedlik PH, Smithers JA, Sedman AJ, Stern RH. Atorvastatin pharmacokinetic interactions with other CYP3A4 substrates: erythromycin and ethinyl estradiol [abstract]. Pharm Res 1996;13:S437.
  53. Muck W, Ochmann K, Rohde G, Unger S, Kuhlmann J. Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the IIMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol 1998;53:469-73.[Medline]
  54. Bradford RH, Shear CL, Chremos AN, Dujovne CA, Franklin FA, Grillo RB, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up. Am J Cardiol 1994;74:667-73.[Medline]
  55. 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.[Medline]
  56. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother 1995;29:743-59.[Abstract]
  57. Ballantyne CM, Bourge RC, Domalik LJ, Eisen HJ, Fishbein DP, Kubo SH, et al. Treatment of hyperlipidemia after heart transplantation and rationale for the heart transplant lipid registry. J Am Coll Cardiol 1996;78:532-5.
  58. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol 1995;76:80A-83A.[Medline]
  59. Scalvini T, Marocolo D, Cerudelli B, Sleiman I, Balestrieri GP, Giustina G. Pravastatin-associated myopathy. Report of a case. Recenti Prog Med 1995;86:198-200.[Medline]
  60. Galiana J, Marchan E, Montes I, Pato S. Toxic myopathies related to the administration of hypolipidemic agents: Are the drugs the only things responsible? Rev Clin Esp 1995;195:620-2.[Medline]
  61. Lang JE, Wang P, Glueck CJ. Myopathy associated with lipid lowering therapy in patients with previously undiagnosed or undertreated hypothyroidism. Clin Chim Acta 1996;254:65-92.[Medline]
  62. Hino I, Akama H, Furuya T, Ueda H, Taniguchi A, Hara M, et al. Pravastatin-induced rhabdomyolysis in a patient with mixed connective tissue disease. Arthritis Rheum 1996;39:1259-60.[Medline]
  63. Giordano N, Senesi M, Mattii G, Battisti E, Villanova M, Gennari C. Polymyositis associated with simvastatin. Lancet 1997;349(9065):1600-1.[Medline]



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