Summary
The hypolipidaemic agent pravastatin differs from other US Food and Drug Administration (FDA)-approved HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin) because it has greater hydrophilicity, as a result of the hydroxyl group attached to its decalin ring. The hydrophilic nature of pravastatin accounts for its minimal penetration into the intracellular space of nonhepatic tissues, including an apparent inability to cross the blood-brain barrier. The drug is also well tolerated because it is rapidly absorbed and excreted, and does not accumulate in plasma even with repeated administration.
Pravastatin is taken up into the liver by an active transport carrier system, and the hepatic extraction ratio is high (0.66). The drug and its metabolites are cleared through both hepatic and renal routes (53 and 47%, respectively). The dual route of elimination reduces the need for dosage adjustment if the function of either of these organs is impaired. Dosage adjustments are also not required on the basis of age or gender. Furthermore, the drug can be given without regard to food intake, an important consideration for compliance since lipid-lowering therapy is generally required long term.
The drug is approximately 50% protein bound, and, therefore, compared with other members of its class the tendency for displacement of highly protein bound drugs such as warfarin is decreased. This minimal potential for drug-drug interactions is important for patients who are taking multiple drugs because of concomitant medical problems. However, as with any HMG-CoA reductase inhibitor, caution should be exercised when pravastatin is given with nicotinic acid (niacin), gemfibrozil or cyclosporin, because of increased risk for myopathy in patients receiving combination therapy.
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References
Gagné C, Moorjani S, Brun D, et al. Heterozygous familial hypercholesterolemia and the relationship between plasma lipids, lipoproteinemias, clinical manifestations and ischemic heart disease in men and women. Atherosclerosis 1979; 34: 13–24
Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 1969; 2: 1380–2
LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Circulation 1990; 81: 1721–33
Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251: 351–64
Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365–74
Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641–51
Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with cholestyramine in progression of coronary arteriosclerosis: Results of the NHLBI Type II Coronary Intervention Study. Circulation 1984; 69: 313–24
Levy RI, Brensike JF, Epstein SE, et al. The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: Results of the NHLBI Type II Coronary Intervention Study. Circulation 1984; 69: 325–37
Canner PL, Berge KG, Werger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long term benefits with niacin. J Am Coll Cardiol 1986; 8: 1245–55
Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987; 257: 3233–40
Brown G, Albers JJ, Fisher LF, et al. Regression of coronary artery disease as a result of intensive lipid lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289–98
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 (Adult Treatment Panel II). JAMA 1993; 269: 3015–23
Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988; 319: 24–32
Witzum JL. Current approaches to drug therapy for the hypercholesterolemic patient. Circulation 1989; 80: 1101–14
Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62 Suppl.: 28J–34J
Jones PH. Lovastatin and simvastatin prevention studies. Am J Cardiol 1990; 66 Suppl.: 39B–49B
McGovern ME, Mellies MJ. Long-term experience with pravastatin in clinical research trials. Clin Ther 1993; 15: 57–64
Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J Antibiot (Tokyo) 1976; 29: 1346–8
Gordon DT, Rifkind BM. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: a new class of cholesterol-lowering agents. Ann Intern Med 1987; 107: 759–61
Illingworth DR. Clinical implications of new drugs for lowering plasma cholesterol concentrations. Drugs 1991; 41: 151–60
Alberts AW. Discovery, biochemistry and biology of lovastatin. Am J Cardiol 1988; 62: 10J–15J
Gotto AM Jr. Pravastatin: a hydrophilic inhibitor of cholesterol synthesis. J Drug Dev 1990; 3: 155–61
Levy RI, Troendle AJ, Fattu JM. A quarter century of drug treatment of dyslipoproteinemia with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation 1993; 87 (Suppl. III): III–45–III–53
Nakaya N, Homma Y, Tamachi H, et al. The effect of CS-514, an inhibitor of HMG-CoA reductase, on serum lipids in healthy volunteers. Atherosclerosis 1986; 61: 125–8
Nakaya N, Homma Y, Tamachi H, et al. The effect of CS-514 on serum lipids and apolipoproteins in hypercholesterolemic subjects. JAMA 1987; 257: 3088–93
Jones PH, Farmer JA, Cressman MD, et al. Once-daily pravastatin in patients with primary hypercholesterolemia: a dose-response study. Clin Cardiol 1991; 14: 146–51
Hunninghake DB, Knopp RH, Schonfeld G, et al. Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. Atherosclerosis 1990; 85: 81–9
Pravastatin. ER Squibb & Sons, Prescribing Information, Princeton, USA, 1993
Funke PT, Ivashkiv E, Arnold ME, et al. Determination of pravastatin sodium and its major metabolite in human serum/plasma by capillary gas chromatography/negative ion chemical ionization mass spectrometry. Biomed Environ Mass Spectr 1989; 18: 904–9
Everett DW, Chando TJ, Didonato GC, et al. Biotransformation of pravastatin sodium in humans. Drug Metab Dispos 1991; 19: 740–8
Pentikainen PJ, Saraheimo M, Schwartz JI, et al. Comparative pharmacokinetics of lovastatin, simvastatin and pravastatin in humans. J Clin Pharmacol 1992; 32: 136–40
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
Tobert SA, Shear CL, Chremos AN, et al. Clinical experience with lovastatin. Am J Cardiol 1990; 65: 23F–26F
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
Pan HY, DeVault AR, Wang-Iverson D. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J Clin Pharmacol 1990; 30: 1128–35
Pan HY, Willard DA, Funke PT, et al. The clinical pharmacology of SQ 31,000 (CS 514) in healthy subjects. In: Paoletti R, Kritchevsky D, Holmes WL, editors. Drugs affecting lipid metabolism. Berlin: Springer-Verlag, 1987: 255–9
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
Pan HY. Clinical pharmacology of pravastatin, a selective inhibitor of HMG-CoA reductase. Eur J Clin Pharmacol 1991; 40 Suppl.1: S15–S18
Pan HY, DeVault AR, Brescia D, et al. Effects of food on pravastatin pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther Toxicol 1993; 31: 291–4
Manufacturer information. Mevacor: lovastatin. West Point: Merck & Co. 1992
Pravastatin Multicenter Study Group. II. Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Arch Intern Med 1993; 153: 1321–9
Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195–202
Yamazaki M, Suzuki H, Hanano M, et al. Na+-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am J Physiol 1993; 264: G36–G44
Scott WA, Mahoney EM, Mosley ET. Mechanism of action and differential pharmacology of pravastatin, a hydrophilic and selective HMG-CoA-reductase inhibitor. In: LaRosa JC, editor. New advances in the control of lipid metabolism: focus on pravastatin. London: Royal Society of Medicine Services, 1989: 1–8
Koga T, Fukuda K, Shimada Y, et al. Lovastatin and simvastatin: The relationship between inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rat. Eur J Biochem 1992; 209: 315–9
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
Halstenson CE, Triscari J, DeVault AR, et al. Single dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment. J Clin Pharmacol 1989; 32: 124–32
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
Pan H, Funke P, Waclawski A, et al. Comparative pharmacokinetics of pravastatin, an HMG CoA reductase inhibitor, in healthy elderly and young male subjects [abstract]. J Clin Pharmacol 1989; 29: 848
Pan HY, 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
Pan HY. HMG-CoA reductase inhibitors: clinical pharmacology. In: Gotto AM Jr., Mancini M, Richter WO, eds. Treatment of severe hypercholesterolemia in prevention of coronary heart disease — 2. Proceedings 2nd international symposium, June, Munich 1989. Basel: Karger, 1990: 66–70
Hunninghake DB, Mollies MJ, Goldberg AC, et al. Efficacy and safety of pravastatin in patients with primary hypercholesterolemia II. Once-daily versus twice-daily dosing. Atherosclerosis 1990; 85: 219–27
Vgontzas AN, Kales A, Bixler ED, et al. Effects of lovastatin and pravastatin on sleep efficiency and sleep stages. Clin Pharmacol Ther 1991; 50: 730–7
Partinen M, Pihl S, Strandberg T, et al. Comparisons of effects of sleep on lovastain and pravastatin in hypercholesterolaemia. Am J Cardiol 1994; 73: 876–80
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Quion, J.A.V., Jones, P.H. Clinical Pharmacokinetics of Pravastatin. Clin. Pharmacokinet. 27, 94–103 (1994). https://doi.org/10.2165/00003088-199427020-00002
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DOI: https://doi.org/10.2165/00003088-199427020-00002