Atorvastatin

Atorvastatin
Systematic (IUPAC) name
(3R,5R)-7-[2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Clinical data
Trade names Lipitor, Atorva
AHFS/Drugs.com monograph
MedlinePlus a600045
Licence data US Daily Med:link
  • AU: D
  • US: X (Contraindicated)
Oral
Pharmacokinetic data
Bioavailability 12%
Metabolism Hepatic - CYP3A4
Half-life 14 h
Excretion Bile
Identifiers
134523-00-5 Yes
C10AA05
PubChem CID 60823
DrugBank APRD00055 
ChemSpider 54810 Yes
UNII A0JWA85V8F 
KEGG D07474 Yes
ChEBI CHEBI:39548 Yes
ChEMBL CHEMBL1487 Yes
PDB ligand ID 117 (PDBe, RCSB PDB)
Chemical data
Formula C33H35FN2O5
558.64
  (what is this?)  (verify)

Atorvastatin (INN) /əˌtɔrvəˈstætən/, marketed by Pfizer as a calcium salt under the trade name Lipitor,[1] is a member of the drug class known as statins, which are used primarily for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.

Atorvastatin was discovered by Bruce Roth and coworkers at Parke-Davis,[2][3] since acquired by Warner-Lambert and then Pfizer.[4][5][6] Although atorvastatin was the fifth drug in the class of statins to be developed, clinical trials showed that atorvastatin caused a more dramatic reduction in LDL-C than the other statin drugs. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug of all time, with more than US$125 billion in sales over approximately 14.5 years.[7]

Pfizer's patent on atorvastatin expired in November 2011.[8]

Medical uses

The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease:[9]

Dyslipidemia

Cardiovascular disease

Other uses

There have been recent studies suggesting that high-dose statin therapy plays a plaque-stabilizing role in patients suffering from acute coronary syndrome and thrombotic stroke.[25][26]

Administration

Atorvastatin may be used in combination with bile acid sequestrants and ezetimibe to increase the reduction in cholesterol levels. However, It is not recommended to combine statin drug treatment with certain other cholesterol-lowering drugs, particularly fibrates, because this may increase the risk of myopathy-related adverse effects.[17]

While many statin medications should be administered at bedtime for optimal effect, atorvastatin can be dosed at any time of day, as long as it is continually dosed once daily at the same time.[27][28]

Specific populations

Contraindications

Adverse effects

Major

Common

The following have been shown to occur in 1–10% of patients taking atorvastatin in clinical trials.

High-dose atorvastatin have also been associated with worsening glycemic control.[37][38]

Interactions

Interactions with clofibrate, fenofibrate, gemfibrozil, which are fibrates used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins, increase the risk of myopathy and rhabdomyolysis.[32][39][40]

Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole,[41] telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, or verapamil,[42] and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant.[30] Often, bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin,[43] which are also CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethindrone and ethinyl estradiol; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.[44]

Antacids can rarely decrease the plasma concentrations of statin drugs, but do not affect the LDL-C-lowering efficacy.[45]

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis.[30]

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.[30]

Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations.[46] Grapefruit juice components are known inhibitors of intestinal CYP3A4.

Co-administration of grapefruit juice with atorvastatin may cause an increase in Cmax and AUC, which can lead to adverse reactions or overdose toxicity.[47]

A few cases of myopathy have been reported when atorvastatin is given with colchicine.[17]

Mechanism of action

Main article: Statin

As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.

Recent studies have shown that in patients suffering from acute coronary syndrome, high-dose statin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. However, there is an increased risk of statin-associated adverse effects with such high-dose statin treatment.[25] There is a similar thought process and risks associated with using high-dose statins to prevent recurrence of thrombotic stroke.[26]

Pharmacodynamics

The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic drug concentration, which correlates with extent of LDL-C reduction.[17]

Pharmacokinetics

Absorption

Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (Tmax) of 1–2 h. The absolute bioavailability of the drug is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose administration is known to reduce the Cmax and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breastmilk.

Metabolism

Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4.

Excretion

Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 h. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 h, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption.[30]

In hepatic insufficiency, plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A-stage liver disease show a four-fold increase in both Cmax and AUC. Patients with B-stage liver disease show a 16-fold increase in Cmax and an 11-fold increase in AUC.

Geriatric patients (>65 years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and Cmax values that are 40% and 30% higher, respectively. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses.[31]

Pharmacogenetics

Several genetic polymorphisms have been found to be associated with a higher incidence of undesirable side effects of atorvastatin. This phenomenon is suspected to be related to increased plasma levels of pharmacologically active metabolites, such as atorvastatin lactone and p-hydroxyatorvastatin. Atorvastatin and its active metabolites may be monitored in potentially susceptible patients using specific chromatographic techniques.[48]

Chemical synthesis

Atorvastatin synthesis in commercial production (process) chemistry. The key step of establishing this drug's stereocenters, through initial use of an inexpensive natural product (chiral pool approach).
Atorvastatin synthesis during discovery chemistry. The key step of establishing stereocenters, using of a chiral ester auxiliary approach.

The first synthesis of atorvastatin at Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of the enantiomers. An early enantioselective route to atorvastatin made use of an ester chiral auxiliary to set the stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction.[3][49] Once the compound entered pre-clinical development, process chemistry developed a cost-effective and scalable synthesis.[3] In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became a key aspect of the overall design. The final commercial production of atorvastatin relied on a chiral pool approach, where the stereochemistry of the first alcohol functional group was carried into the synthesis—through the choice of isoascorbic acid, an inexpensive and easily sourced plant-derived natural product.[3][50]

Formulations

Pack and tablet of atorvastatin (Lipitor) 40mg

Atorvastatin calcium tablets are marketed by Pfizer under the trade name Lipitor[51] for oral administration. Tablets are white, elliptical, and film-coated. Pfizer also packages the drug in combination with other drugs, such as with Caduet.[52] Pfizer recommends that patients do not break tablets in half to take half-doses, even when this is recommended by their doctors.

Generic availability

Pfizer's U.S. patent on Lipitor expired on 30 November 2011.[8] Initially, generic atorvastatin was manufactured only by Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers began to supply the drug in May 2012.[53]

In other countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Stator, Atorvastatin Teva, Litorva, Torid, Atoris, Atorlip, Mactor, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.[54] Pfizer also makes its own generic version under the name Zarator, which is the sole Pharmac-subsidised brand of atorvastatin in New Zealand.[55]

Drug recall

On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1 mm in size). The FDA received no reports of injury from the contamination.[56]

References

  1. ↑ "Pfizer product promotion page (Lipitor)". Retrieved 2011-12-05.
  2. ↑ US patent 4681893, Roth BD, "Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis", issued 1987-07-21
  3. ↑ 3.0 3.1 3.2 3.3 Roth BD (2002). "The discovery and development of atorvastatin, a potent novel hypolipidemic agent". Prog Med Chem. Progress in Medicinal Chemistry 40: 1–22. doi:10.1016/S0079-6468(08)70080-8. ISBN 978-0-444-51054-9. PMID 12516521.
  4. ↑ Milton L. Hoefle (2000). "The Early History of Parke-Davis and Company" (PDF). Bull. Hist. Chem. 25 (1): 28–34.
  5. ↑ "Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion". New York Times. 2000.
  6. ↑ John Simons (20 January 2003). "The $10 Billion Pill Hold the fries, please. Lipitor, the cholesterol-lowering drug, has become the bestselling pharmaceutical in history. Here's how Pfizer did it". Fortune Magazine.
  7. ↑ "Lipitor becomes world's top-selling drug". Crain's New York Business. 2011-12-28.
  8. ↑ 8.0 8.1 CNN Wire Staff (30 November 2011). "Lipitor loses patent, goes generic". CNN. Retrieved 18 November 2012.
  9. ↑ "Atorvastatin Calcium". Drugs.com. Retrieved 3 April 2011.
  10. ↑ 10.0 10.1 10.2 McCrindle BW, Ose L, Marais AD (July 2003). "Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial". J. Pediatr. 143 (1): 74–80. doi:10.1016/S0022-3476(03)00186-0. PMID 12915827.
  11. ↑ Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM (April 2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". Journal of the American Medical Association 295 (13): 1556–65. doi:10.1001/jama.295.13.jpc60002. PMID 16533939.
  12. ↑ Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, Jones PH, Haber HE, Black DM (May 1995). "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. 15 (5): 678–82. doi:10.1161/01.ATV.15.5.678. PMID 7749881.
  13. ↑ Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM (January 1996). "Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia". Journal of the American Medical Association 275 (2): 128–33. doi:10.1001/jama.1996.03530260042029. PMID 8531308.
  14. ↑ Ozaki K, Kubo T, Imaki R, Shinagawa H, Fukaya H, Ohtaki K, Ozaki S, Izumi T, Aizawa Y (August 2006). "The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia". J. Atheroscler. Thromb. 13 (4): 216–9. doi:10.5551/jat.13.216. PMID 16908955.
  15. ↑ Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J (August 1997). "Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia". Arterioscler. Thromb. Vasc. Biol. 17 (8): 1527–31. doi:10.1161/01.ATV.17.8.1527. PMID 9301631.
  16. ↑ 16.0 16.1 Rossi S, ed. (2006). Australian medicines handbook 2006. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10 17.11 17.12 "LIPITOR (atorvastatin calcium) Tablets for oral administration" (PDF). Full Prescribing Information. Pfizer Inc. Retrieved 18 April 2014.
  18. ↑ Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J (April 2003). "Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial". Lancet 361 (9364): 1149–58. doi:10.1016/S0140-6736(03)12948-0. PMID 12686036.
  19. ↑ Law MR, Wald NJ, Rudnicka AR (June 2003). "Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis". BMJ 326 (7404): 1423. doi:10.1136/bmj.326.7404.1423. PMC 162260. PMID 12829554.
  20. ↑ Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB (May 1998). "Prediction of coronary heart disease using risk factor categories" (PDF). Circulation 97 (18): 1837–47. doi:10.1161/01.CIR.97.18.1837. PMID 9603539.
  21. ↑ Jones P, Kafonek S, Laurora I, Hunninghake D (March 1998). "Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)". American Journal of Cardiology 81 (5): 582–7. doi:10.1016/S0002-9149(97)00965-X. PMID 9514454.
  22. ↑ Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH (2004). "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial". Lancet 364 (9435): 685–96. doi:10.1016/S0140-6736(04)16895-5. PMID 15325833.
  23. ↑ Neil HA, DeMicco DA, Luo D, Betteridge DJ, Colhoun HM, Durrington PN, Livingstone SJ, Fuller JH, Hitman GA (November 2006). "Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS)". Diabetes Care 29 (11): 2378–84. doi:10.2337/dc06-0872. PMID 17065671.
  24. ↑ Gentile S, Turco S, Guarino G, Sasso CF, Amodio M, Magliano P, Salvatore T, Corigliano G, Agrusta M, De Simone G, Gaeta I, Oliviero B, Torella R (December 2000). "Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia". Diabetes Obes Metab 2 (6): 355–62. doi:10.1046/j.1463-1326.2000.00106.x. PMID 11225965.
  25. ↑ 25.0 25.1 Rosa GM, Carbone F, Parodi A, Massimelli EA, Brunelli C, Mach F, Vuilleumier N, Montecucco F (2014). "Update on the efficacy of statin treatment in acute coronary syndromes". Eur. J. Clin. Invest. 44 (5): 501–15. doi:10.1111/eci.12255. PMID 24601937.
  26. ↑ 26.0 26.1 Furie KL (2012). "High-dose statins should only be used in atherosclerotic strokes". Stroke 43 (7): 1994–5. doi:10.1161/STROKEAHA.111.633339. PMID 22581818.
  27. ↑ "Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)". JAMA 285 (19): 2486–97. 2001. doi:10.1001/jama.285.19.2486. PMID 11368702.
  28. ↑ Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ (2004). "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines". Circulation 110 (2): 227–39. doi:10.1161/01.CIR.0000133317.49796.0E. PMID 15249516.
  29. ↑ Hermann M, Bogsrud MP, Molden E, Asberg A, Mohebi BU, Ose L, Retterstøl K (June 2006). "Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy". Clin. Pharmacol. Ther. 79 (6): 532–9. doi:10.1016/j.clpt.2006.02.014. PMID 16765141.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Williams D, Feely J (2002). "Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors". Clin Pharmacokinet 41 (5): 343–70. doi:10.2165/00003088-200241050-00003. PMID 12036392.
  31. ↑ 31.0 31.1 31.2 31.3 31.4 Lipitor: Prescribing Information. Pfizer. June 2009.
  32. ↑ 32.0 32.1 Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP (March 1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226–9. doi:10.1002/j.1552-4604.1993.tb03948.x. PMID 8463436.
  33. ↑ http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm#3
  34. ↑ http://www.webmd.com/cholesterol-management/news/20120109/statins-may-raise-diabetes-risk-in-older-women
  35. ↑ http://circ.ahajournals.org/content/126/18/e282.full
  36. ↑ http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm
  37. ↑ Mayo Clinic Staff. "Statin Side Effects: Weigh the Risks and Benefits". The Mayo Clinic. Retrieved 19 April 2014.
  38. ↑ Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS (September 2010). "Do statins beneficially or adversely affect glucose homeostasis?". Curr Vasc Pharmacol 8 (5): 612–31. doi:10.2174/157016110792006879. PMID 20507274.
  39. ↑ Steiner G (December 2007). "Atherosclerosis in type 2 diabetes: a role for fibrate therapy?". Diab Vasc Dis Res 4 (4): 368–74. doi:10.3132/dvdr.2007.067. PMID 18158710.
  40. ↑ Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R (December 2004). "Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs". Journal of the American Medical Association 292 (21): 2585–90. doi:10.1001/jama.292.21.2585. PMID 15572716.
  41. ↑ Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P (October 2000). "Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin". Clin. Pharmacol. Ther. 68 (4): 391–400. doi:10.1067/mcp.2000.110537. PMID 11061579.
  42. ↑ Neuvonen PJ, Niemi M, Backman JT (December 2006). "Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance". Clin. Pharmacol. Ther. 80 (6): 565–81. doi:10.1016/j.clpt.2006.09.003. PMID 17178259.
  43. ↑ Backman JT, Luurila H, Neuvonen M, Neuvonen PJ (August 2005). "Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites". Clin. Pharmacol. Ther. 78 (2): 154–67. doi:10.1016/j.clpt.2005.04.007. PMID 16084850.
  44. ↑ "Lipitor". U.S. National Library of Medicine.
  45. ↑ McKenney JM (2005). "Efficacy and safety of rosuvastatin in treatment of dyslipidemia". Am J Health Syst Pharm 62 (10): 1033–47. PMID 15901588.
  46. ↑ Schwartz JB (February 2009). "Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence". Clin. Pharmacol. Ther. 85 (2): 198–203. doi:10.1038/clpt.2008.165. PMID 18754003.
  47. ↑ Kane GC, Lipsky JJ (September 2000). "Drug-grapefruit juice interactions". Mayo Clinic Proceedings 75 (9): 933–42. doi:10.4065/75.9.933. PMID 10994829.
  48. ↑ Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, Fuller JH, Livingstone S, Charlton-Menys V, Neil A, Poulter N, Sever P, Shields DC, Stanton AV, Chatterjee A, Hyde C, Calle RA, Demicco DA, Trompet S, Postmus I, Ford I, Jukema JW, Caulfield M, Hitman GA (May 2012). "Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)". J Lipid Res 53 (5): 1000–1011. doi:10.1194/jlr.P021113. PMC 3329377. PMID 22368281.
  49. ↑ Roth BD, Blankley CJ, Chucholowski AW, Ferguson E, Hoefle ML, Ortwine DF, Newton RS, Sekerke CS, Sliskovic DR, Wilson M (1991). "Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus". J. Med. Chem. 34: 357–366. doi:10.1021/jm00105a056..
  50. ↑ Jie Jack Li, Douglas S. Johnson, Drago R. Sliskovic, Bruce D. Roth (2004). "Chapter 9. Atorvastatin Calcium (Lipitor)". Contemporary Drug Synthesis. John Wiley & Sons, Inc. pp. 113–125. ISBN 0-471-21480-9..
  51. ↑ Medical Product Reviews. "Atorvastatin Calcium (Lipitor Tablets) - Uses, Dosage and Side Effects". Retrieved 3 May 2012.
  52. ↑ News Medical. "Lipitor - What is Lipitor?". Retrieved 3 May 2012.
  53. ↑ "Price to UK for 28 tablets from £3.25 (10mg) to £10.00 (80mg)". National Health Service. June 2012.
  54. ↑ "Pfizer 2008 Annual Report" (PDF). Pfizer. 23 April 2009. Retrieved 7 August 2009.
  55. ↑ Rapley, Lisa (31 May 2012). "Atorvastatin sole funding announced". PharmacyToday.co.nz. Retrieved 16 July 2014.
  56. ↑ "FDA Statement on Ranbaxy Atorvastatin Recall". FDA. Retrieved 19 April 2014.

Further reading

External links