Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin

Journal of Clinical Pharmacology

Volumn 51, Issue 3, 2011, Pages 378-388

  Whitfield, Lloyd R ^a   Porcari, Anthony R ^b   Alvey, Christine ^b   Abel, Robert ^a   Bullen, William ^b   Hartman, Daniel ^a  

^a PFIZER INC   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Atorvastatin; drug interactions; fenofibrate; gemfibrozil; pharmacokinetics

Indexed keywords

2 HYDROXYATORVASTATIN; 2 HYDROXYATORVASTATIN LACTONE; 4 HYDROXYATORVASTATIN LACTONE; ATORVASTATIN; DRUG METABOLITE; FENOFIBRATE; GEMFIBROZIL; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ADULT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DISEASE SEVERITY; DIZZINESS; DRUG EFFECT; DRUG HALF LIFE; DRUG SAFETY; FEMALE; FLATULENCE; HEADACHE; HUMAN; HUMAN EXPERIMENT; INFECTION; MALE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NORMAL HUMAN; PAIN; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; SOMNOLENCE; TIME TO MAXIMUM PLASMA CONCENTRATION; VOMITING;

ADULT; BIOTRANSFORMATION; CROSS-OVER STUDIES; DRUG INTERACTIONS; ENZYME INHIBITORS; FEMALE; FENOFIBRATE; GEMFIBROZIL; HALF-LIFE; HEPTANOIC ACIDS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERLIPIDEMIAS; HYPOLIPIDEMIC AGENTS; LACTONES; MALE; MIDDLE AGED; PYRROLES;

EID: 79953813165     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1177/0091270010366446     Document Type: Article

References (28)

1. Vasudevan AR, Jones PH. Effective use of combination lipid therapy. Curr Cardiol Rep. 2005;7:471-479. (Pubitemid 41700658)
2. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565-581. (Pubitemid 44908269)
3. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72:685-691. (Pubitemid 36021007)
4. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122-129. (Pubitemid 30659167)
5. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69:340-345. (Pubitemid 32477075)
6. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther. 2003;73:538-544. (Pubitemid 37249124)
7. Schneck DW, Birmingham BK, Zalikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455-463. (Pubitemid 38534566)
8. 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.
9. Bergman AJ, Murphy G, Burke J, et al. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol. 2004;44:1054-1062. (Pubitemid 39096820)
10. 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;40:316-323.
11. Martin PD, Dane AL, Schneck DW, Warwick MJ. An openlabel, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther. 2003;25:459-471. (Pubitemid 36286913)
12. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78:154-167. (Pubitemid 41112284)
13. Penn R, Williams RX III, Guha-Ray DK, Sawyers WG, Braun SL, Rains KT. An open-label, crossover study of the pharmacokinetics of insoluble drug delivery-microparticle fenofibrate in combination with atorvastatin, simvastatin, and extended-release niacin in healthy volunteers. Clin Ther. 2006;28:45-54. (Pubitemid 43254989)
14. Kearney AS, Crawford LF, Mehta SC, Radebaugh GW. The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm Res. 1993;10:1461-1465. (Pubitemid 23302663)
15. Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30:505-512. (Pubitemid 34456970)
16. Goosen TC, Bauman JN, Davis JA, et al. Atorvastatin glucuronidation is minimally and nonselectively inhibited by the fibrates gemfibrozil, fenofibrate, and fenofibric acid. Drug Metab Dispos. 2007;35:1315-1324. (Pubitemid 47121772)
17. Jacobsen W, Kuhn B, Soldner A, et al. Lactonization is the critical first step in the disposition of the 3-hydroxy-3- methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos. 2000;28:1369-1378.
18. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81:194-204. (Pubitemid 46174816)
19. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82:726-733. (Pubitemid 350114817)
20. Wu X, Whitfield LR, Stewart BH. Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res. 2000;17:209-215. (Pubitemid 30158371)
21. Chen C, Mireles RJ, Campbell SD, et al. Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos. 2005;33:537-546.
22. Chen C, Lin J, Smolarek T, Tremaine L. P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice. Drug Metab Dispos. 2007;35:1725-1729. (Pubitemid 47481596)
23. Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M. ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther. 2008;84:457-461.
24. Yamazaki M, Li B, Louie SW, et al. Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica. 2005;35:737-753. (Pubitemid 41441523)
25. Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol. 2005;97:249-256. (Pubitemid 41433700)
26. Sakaeda T, Fujino H, Komoto C, et al. Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharm Res. 2006;23:506-512.
27. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280-1287. (Pubitemid 35265837)
28. Goldberg AC, Bays HE, Ballantyne CM, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia. Am J Cardiol. 2009;103:515-522.