Pharmaceutical Research

, Volume 22, Issue 1, pp 71–78

Comparative Effects of Fibrates on Drug Metabolizing Enzymes in Human Hepatocytes

  • Thomayant Prueksaritanont
  • Karen M. Richards
  • Yue Qiu
  • Kristine Strong-Basalyga
  • Alisha Miller
  • Chunze Li
  • Roy Eisenhandler
  • Edward J. Carlini

No Heading


The induction potential of different fibric acid derivatives on human drug metabolizing enzymes was evaluated to help assess the role of enzyme induction on pharmacokinetic drug interactions.


Effects of gemfibrozil, fenofibric acid, and clofibric acid on expression levels of cytochromes P450 (CYPs) 3A4 and 2C8 and UDP-glucuronyltransferase (UGT) 1A1 were evaluated in primary human hepatocyte cultures. The potential for these fibrates to activate human pregnane X receptor (PXR) also was studied in a cell-based PXR reporter gene assay.


All three fibrates caused increases in mRNA levels of CYP3A4 (2- to 5-fold), CYP2C8 (2- to 6-fold), and UGT1A1 (2- to 3-fold). On average, the effects on CYP3A4 were less than (≤30% of rifampin), while those on CYP2C8 and UGT1A1 were comparable to or slightly higher than (up to 200% of rifampin) the corresponding effects observed with rifampin (10 μM). Consistent with the mRNA results, all fibrates caused moderate (<2- to 3-fold) increases in CYP3A4 activity (measured by testosterone 6β hydroxylase), as compared to about a 10-fold increase by rifampin. Significant increases (3- to 6-fold) in amodiaquine N-deethylase (a functional probe for CYP2C8 activity) also were observed with clofibric acid, fenofibric acid, and rifampin, in agreement with the mRNA finding. However, in contrast to the mRNA induction, marked decreases (>60%) in CYP2C8 activity were obtained with gemfibrozil treatment. Consistent with this finding, co-incubation of amodiaquine with gemfibrozil, but not with fenofibric acid, clofibric acid, or rifampin, in human liver microsomes or hepatocytes resulted in significantly decreased amodiaquine N-deethylase activity (IC50 = 80 μM for gemfibrozil, >500 μM for fenofibric or clofibric acid, and >50 μM for rifampin). Similar to rifampin, all three fibrates caused a modest change in the glucuronidation of chrysin, a nonspecific substrate of UGTs. No significant activation on human pregnane X receptor (PXR) was observed with the three fibrates in a PXR reporter gene assay.


In human hepatocytes, both fenofibric acid and clofibric acid are inducers of CYP3A4 and CYP2C8. Gemfibrozil is also an inducer of CYP3A4, but acts as both an inducer and an inhibitor of CYP2C8. In this system, all fibrates are weak inducers of UGT1A1. The enzyme inducing effects of fibrates appear to be mediated via a mechanism(s) other than PXR activation. These results suggest that fibrates may have potential to cause various pharmacokinetic drug interactions via their differential effects on enzyme induction and/or inhibition.

Key words:

clofibrate clofibric acid CYP2C8 CYP3A4 enzyme induction enzyme inhibition fenofibrate fenofibric acid fibrates gemfibrozil rifampin statins UGT1A 



cytochrome P450


ligand binding domain


minimum essential medium


human pregnane X receptor




Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    1. D. J. Rader and S. M. Haffner. Roles of fibrates in the management of hypertriglyceridemia. Am. J. Cardiol. 83:30F–35F (1999).Google Scholar
  2. 2.
    2. A. Lozada and C. A. Dujovne Drug interactions with fibric acids. Pharmacol. Ther. 63:163–176 (1994).Google Scholar
  3. 3.
    3. D. B. Miller and J. D. Spence. Clinical pharmacokinetics of fibric acid derivatives (Fibrates). Clin. Pharmacokinet. 34:155–162 (1998).Google Scholar
  4. 4.
    4. J. T. Backman, C. Kyrklund, K. T. Kivistö, J.-S. Wang, and P. J. Neuvonen. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin. Pharmacol. Ther. 68:122–129 (2000).Google Scholar
  5. 5.
    5. C. Kyrklund, J. T. Backman, K. T. Kivistö, M. Neuvonen, J. Laitila, and P. J. Neuvonen. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin. Pharmacol. Ther. 69:340–345 (2001).Google Scholar
  6. 6.
    6. J. T. Backman, C. Kyrklund, M. Neuvonen, and P. J. Neuvonen. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin. Pharmacol. Ther. 72:685–691 (2002).Google Scholar
  7. 7.
    7. C. Kyrklund, J. T. Backman, M. Neuvonen, and P. J. Neuvonen. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin. Pharmacol. Ther. 73:538–544 (2003).Google Scholar
  8. 8.
    8. T. Prueksaritanont, J. Zhao, and B. Ma. Mechanistic studies on the metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301:1042–1051 (2002).Google Scholar
  9. 9.
    9. T. Prueksaritanont, C. Tang, Y. Qiu, L. Mu, R. Subramanain, and J. H. Lin. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos. 30:1280–1287 (2002).Google Scholar
  10. 10.
    10. T. Prueksaritanont, L. M. Gorham, and B. Ma. In vitro metabolism of simvastatin in humans: identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab. Dispos. 25:1191–1199 (1997).Google Scholar
  11. 11.
    11. J. A. Farmer. Learning from the cerivastatin experience. Lancet 358:1383–1385 (2001).CrossRefPubMedGoogle Scholar
  12. 12.
    12. K. Rašlová, D. Dubovská, V. Mongiellová, and T. Trnovec. Relationship between plasma fenofibric acid levels and the effect of micronized fenofibrate on cholesterol, low-density-lipoprotein cholesterol and apolipoprotein B in patients with primary hypercholesterolemia. Eur. J. Clin. Pharmacol. 52:101–106 (1997).Google Scholar
  13. 13.
    13. J. Sahi M. A. Milad, and X. Zheng. Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. J. Pharmacol. Exp. Ther. 306:1027–1034 (2003).Google Scholar
  14. 14.
    14. J. Sahi, C. B. Black, and G. A. Hamilton. Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab. Dispos. 31:439–446 (2003).Google Scholar
  15. 15.
    15. D. J. Greenblatt, L. L. von-Moltke, J. P. Daily, J. S. Harmatz, and R. I. Shader. Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J. Clin. Psychopharmacol. 19:293–296 (1999).Google Scholar
  16. 16.
    16. M. Pfister, L. Labbe, J. F. Lu, S. M. Hammer, J. Mellors, K. K. Bennett, S. Rosenkranz, L. B. Sheiner, and AIDS Clinical Trial Group Protocol 398 Investigators. Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir. Clin. Pharmacol. Ther. 72:133–141 (2002).Google Scholar
  17. 17.
    17. Y. H. Wen, J. Sahi, and E. Urda. Effects of bergamottin on human and monkey drug-metabolizing enzymes in primary cultured hepatocytes. Drug Metab. Dispos. 30:977–984 (2002).Google Scholar
  18. 18.
    18. J. K. Ritter, F. K. Kessler, M. T. Thompson, A. D. Grove, D. J. Auyeung, and R. A. Fisher. Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences. Hepatology 30:476–484 (1999).Google Scholar
  19. 19.
    19. G. Luo, M. Cunningham, and S. Kim. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab. Dispos. 30:795–804 (2002).Google Scholar
  20. 20.
    20. S. Gerbal-Chaloin, J.-M. Pascussi, L. Pichard-Garcia, M. Daujat, F. Waechter, J. M. Fabre, N. Carrere, and P. Maurel. Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab. Dispos. 29:242–251 (2001).Google Scholar
  21. 21.
    21. T. Prueksaritanont, R. Subramanian, and X. Fang. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab. Dispos. 30:505–512 (2001).Google Scholar
  22. 22.
    22. Physician’s Desk Reference. Thompson PDR, New Jersey, 2003, pp. 759.Google Scholar
  23. 23.
    23. B. Blumberg, W. Sabbaagh, H. Juguilon, J. Bolado, C. van Meter, E. Ong, and R. Evan. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Gene Dev 12:3195–3205 (1998).Google Scholar
  24. 24.
    24. J. Lehmann, D. McKee, M. Watson, T. Wilson, J. Moore, and S. Kliewer. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Investig 102:1016–1023 (1998).Google Scholar
  25. 25.
    25. J. Sugatani, K. Yamakawa, and E. Tonda. The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biochem. Pharmacol. 67:989–1000 (2004).Google Scholar
  26. 26.
    26. D. P. Hartley, X. Dai, and Y. D. He. Activators of rat PXR differentially modulate hepatic and intestinal gene expression. Mol. Pharmacol. 65:1159–1171 (2004).Google Scholar
  27. 27.
    27. T. Walle, Y. Otake, A. Galijatovic, J. K. Ritter, and U. K. Walle. Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in the human hepatoma cell line Hep G2. Drug Metab. Dispos. 28:1077–1082 (2000).Google Scholar
  28. 28.
    28. M. D. Green, C. D. King, B. Mojarrabi, P. I. Mackenzie, and T. R. Tephly. Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab. Dispos. 26:507–512 (1998).Google Scholar
  29. 29.
    29. X.-Q. Li, A. Björkman, T. B. Anderson, M. Ridderström, and C. M. Masimirembwa. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J. Pharmacol. Exp. Ther. 300:399–407 (2002).Google Scholar
  30. 30.
    30. A. Galijatovic. U. K. Walle, and T. Walle. Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells. Xenobiotica 29:1241–1256 (1999).Google Scholar
  31. 31.
    31. B. Goodwin, E. Hodgson, and C. Liddle. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampin through a distal enhancer module. Mol. Pharmacol. 56:1329–1339 (1999).Google Scholar
  32. 32.
    32. L. Richert, C. Lamboley, and C. Viollon-Abadie. Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes. Toxicol. Appl. Pharmacol. 191:130–146 (2003).Google Scholar
  33. 33.
    33. M. G. Soars, D. M. Petullo, J. A. Eckstein, S. C. Kasper, and S. A. Wrighton. An assessment of UDP-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab. Dispos. 32:140–148 (2004).Google Scholar
  34. 34.
    34. V. Meunier, M. Bourrié, B. Julian, E. Marti, F. Guillou, Y. Berger, and G. Fabre. Expression and induction of CYP1A1/1A2, CYP2A6 and CYP3A4 in primary cultures of human hepatocytes: a 10-year follow-up. Xenobiotica 30:589–607 (2000).Google Scholar
  35. 35.
    35. A. J. Bergman, G. Murphy, J. Burke, J. J. Zhao, R. Valesky, L. Liu, K. C. Lasseter, W. He, T. Prueksaritanont, Y. Qiu, A. Hartford, J. M. Vega, and J. F. Paolini. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J. Clin. Pharmacol. 44:1054–1062 (2004).Google Scholar
  36. 36.
    36. P. Mathew, T. Cuddy, W. G. Tracewell, and D. Salazar. An open-label study on the pharmacokinetics (PK) of pitavastatin (NK-104) when administered concomitantly with fenofibrate or gemfibrozil in healthy volunteers. Clin. Pharmacol. Ther. 75:33 (2004).Google Scholar
  37. 37.
    37. H. Fujino, I. Yamada, S. Shimada, M. Yoneda, and J. Kojima. Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltransferase enzymes involved in lactonization. Xenobiotica 33:27–41 (2003).Google Scholar
  38. 38.
    38. T. Prueksaritanont, B. Ma, and N. Yu. Human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, not CYP2D6. Br. J. Clin. Pharmacol. 56:120–124 (2003).Google Scholar
  39. 39.
    39. J. Y. Park, K. A. Kim, M. H. Kang, S. L. Kim, and J. G. Shin. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin. Pharmacol. Ther. 75:157–162 (2004).Google Scholar
  40. 40.
    40. Z. Dvořák k, M. Modrianský, and L. Pichard-Garcia. Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Mol. Pharmacol. 64:160–169 (2003).Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Thomayant Prueksaritanont
    • 1
  • Karen M. Richards
    • 1
  • Yue Qiu
    • 1
  • Kristine Strong-Basalyga
    • 1
  • Alisha Miller
    • 1
  • Chunze Li
    • 1
  • Roy Eisenhandler
    • 1
  • Edward J. Carlini
    • 1
  1. 1.Department of Drug MetabolismMerck Research LaboratoriesWest PointUSA

Personalised recommendations