Skip to main content

Advertisement

SpringerLink
Log in

Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The aim of this study was to characterise the role of the efflux transporter P-glycoprotein in the disposition of cerivastatin. We investigated directional transport characteristics of [14C]cerivastatin across cell monolayers expressing P-glycoprotein (Caco-2 and L-MDR1) and disposition of cerivastatin in mice with disrupted mdr1a and mdr1b genes. The mice were given orally 1 mg/kg cerivastatin and plasma and tissue samples for analysis of cerivastatin were obtained 10, 20, or 30 min after drug administration. Four knock-out mice and four wild-type mice were studied at each time point. In addition, the hypothesis that gemfibrozil-mediated inhibition of P-glycoprotein contributes to the interaction between gemfibrozil and cerivastatin was tested in Caco-2 cells. The apparent permeability coefficient (Papp) value for the basal-to-apical transport of cerivastatin in Caco-2 and L-MDR1 cell monolayers was 2.4 times (P<0.001) and 3.8 times (P<0.001) as high as the apical-to-basal Papp value respectively. The P-glycoprotein inhibitor PSC-833 (1 μM) inhibited the net basal-to-apical transport of cerivastatin in Caco-2 monolayers by 35% (P<0.01) and the MRP inhibitor MK-571 (10 μM) by 50% (P<0.01). At concentrations up to 250 μM, gemfibrozil showed no significant effects on the net transport of cerivastatin in Caco-2 cells. The concentration of cerivastatin in the brain at 30 min was 3.1 times higher in the knock-out mice than in the wild-type mice (P<0.05). The brain-to-plasma cerivastatin concentration ratio at 20 min and 30 min was 2.1 (P<0.05) and 3.6 times (P<0.05) higher respectively in the knock-out animals compared with the wild-type animals. Collectively, these results indicate that cerivastatin is a P-glycoprotein substrate, although other transporters probably contribute to cerivastatin transport in humans. As several statins are P-glycoprotein substrates, beneficial as well as adverse effects of the statins might be affected by interindividual differences in P-glycoprotein expression or function caused by, e.g., the MDR1 polymorphism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ (2000) Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 68:122–129

    Article  CAS  PubMed  Google Scholar 

  • Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685–691

    Article  CAS  PubMed  Google Scholar 

  • Bischoff H, Heller AH (1998) Preclinical and clinical pharmacology of cerivastatin. Am J Cardiol 82:18J–25J

    Article  CAS  PubMed  Google Scholar 

  • Boberg M, Angerbauer R, Kanhai WK, Karl W, Kern A, Radtke M, Steinke W (1998) Biotransformation of cerivastatin in mice, rats, and dogs in vivo. Drug Metab Dispos 26:640–652

    CAS  PubMed  Google Scholar 

  • Burns M, Duff K (2003) Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer’s disease. Neurochem Res 28:979–986

    Article  CAS  PubMed  Google Scholar 

  • Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR (1990) Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38:1277–1287

    CAS  PubMed  Google Scholar 

  • Evans M, Rees A (2002) Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 25:649–663

    CAS  PubMed  Google Scholar 

  • Fromm MF (2002) The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 54:1295–1310

    Article  CAS  PubMed  Google Scholar 

  • Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W, Schrenk D (2000) The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 157:1575–1580

    CAS  PubMed  Google Scholar 

  • Gaist D, Rodriguez LA, Huerta C, Hallas J, Sindrup SH (2001) Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology 12:565–569

    Google Scholar 

  • Gerk PM, Vore M (2002) Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J Pharmacol Exp Ther 302:407–415

    Article  CAS  PubMed  Google Scholar 

  • Hajjar I, Schumpert J, Hirth V, Wieland D, Eleazer GP (2002) The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J Gerontol A Biol Sci Med Sci 57:M414–M418

    PubMed  Google Scholar 

  • Hirohashi T, Suzuki H, Chu XY, Tamai I, Tsuji A, Sugiyama Y (2000) Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). J Pharmacol Exp Ther 292:265–270

    CAS  PubMed  Google Scholar 

  • Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR (1999) Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 16:408–414

    Article  CAS  PubMed  Google Scholar 

  • König J, Nies AT, Cui Y, Leier I, Keppler D (1999) Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1461:377–394

    PubMed  Google Scholar 

  • Kusuhara H, Sugiyama Y (2002) Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J Control Release 78:43–54

    Article  CAS  PubMed  Google Scholar 

  • Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ (2001) Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 69:340–345

    Article  CAS  PubMed  Google Scholar 

  • Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K (2002) Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain. Arch Neurol 59:213–216

    Article  PubMed  Google Scholar 

  • Lowes S, Cavet ME, Simmons NL (2003) Evidence for a non-MDR1 component in digoxin secretion by human intestinal Caco-2 epithelial layers. Eur J Pharmacol 458:49–56

    Article  CAS  PubMed  Google Scholar 

  • Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33

    Article  CAS  PubMed  Google Scholar 

  • Meissner K, Sperker B, Karsten C, Zu Schwabedissen HM, Seeland U, Bohm M, Bien S, Dazert P, Kunert-Keil C, Vogelgesang S, Warzok R, Siegmund W, Cascorbi I, Wendt M, Kroemer HK (2002) Expression and localization of P-glycoprotein in human heart: effects of cardiomyopathy. J Histochem Cytochem 50:1351–1356

    CAS  PubMed  Google Scholar 

  • Neuvonen PJ, Kantola T, Kivistö KT (1998) Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 63:332–341

    CAS  PubMed  Google Scholar 

  • Omar MA, Wilson JP, Cox TS (2001) Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 35:1096–1107

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, von Richter O, Burk O, Ziegler A, Mettang T, Eichelbaum M, Fromm MF (2000) Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther 293:376–382

    CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Mürdter T, Godel A, Mettang T, Eichelbaum M, Klotz U, Fromm MF (2001) P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin. Naunyn-Schmiedebergs Arch Pharmacol 363:337–343

    Article  CAS  PubMed  Google Scholar 

  • Poirier J (2003) Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol Med 9:94–101

    Article  CAS  PubMed  Google Scholar 

  • Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH (2002a) Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 30:1280–1287

    Article  CAS  PubMed  Google Scholar 

  • Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, Liu L, Lin JH, Pearson PG, Baillie TA (2002b) Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 301:1042–1051

    Article  CAS  PubMed  Google Scholar 

  • Rockwood K, Darvesh S (2003) The risk of dementia in relation to statins and other lipid lowering agents. Neurol Res 25:601–604

    Article  CAS  PubMed  Google Scholar 

  • Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94:4028–4033

    Article  CAS  PubMed  Google Scholar 

  • Schwab M, Eichelbaum M, Fromm MF (2003) Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 43:285–307

    Article  CAS  PubMed  Google Scholar 

  • Shek A, Ferrill MJ (2001) Statin-fibrate combination therapy. Ann Pharmacother 35:908–917

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 304:610–616

    Article  CAS  PubMed  Google Scholar 

  • Staffa JA, Chang J, Green L (2002) Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 346:539–540

    Article  Google Scholar 

  • Taipalensuu J, Tornblom H, Lindberg G, Einarsson C, Sjoqvist F, Melhus H, Garberg P, Sjostrom B, Lundgren B, Artursson P (2001) Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther 299:164–170

    CAS  PubMed  Google Scholar 

  • Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164

    CAS  PubMed  Google Scholar 

  • Thompson PD, Clarkson P, Karas RH (2003) Statin-associated myopathy. J Am Med Assoc 289:1681–1690

    Article  CAS  Google Scholar 

  • Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM (2003) Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 23:871–880

    Article  PubMed  Google Scholar 

  • Wang E, Casciano CN, Clement RP, Johnson WW (2001) HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res 18:800–806

    Article  CAS  PubMed  Google Scholar 

  • Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ (2002) Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 30:1352–1356

    Article  PubMed  Google Scholar 

  • Wu X, Whitfield LR, Stewart BH (2000) Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res 17:209–215

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Robert-Bosch Foundation (Stuttgart), the Deutsche Forschungsgemeinschaft (German Research Foundation, Bonn; FR 1298/2-3) and the Alexander von Humboldt Foundation (Bonn, Germany; M. Niemi).

Author information

Author notes

  1. Martin F. Fromm

    Present address: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany

Authors and Affiliations

  1. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Kari T. Kivistö, Jörg Zukunft, Ute Hofmann, Mikko Niemi, Sabine Rekersbrink, Matthias Schwab, Michel Eichelbaum & Martin F. Fromm

  2. Department of Pharmacology and Toxicology, University of Tübingen, Wilhelmstrasse 56, 72074, Tübingen, Germany

    Swetlana Schneider & Gerd Luippold

Authors
  1. Kari T. Kivistö
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörg Zukunft
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ute Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mikko Niemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabine Rekersbrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Swetlana Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerd Luippold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthias Schwab
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michel Eichelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martin F. Fromm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kari T. Kivistö.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kivistö, K.T., Zukunft, J., Hofmann, U. et al. Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice. Naunyn-Schmiedeberg's Arch Pharmacol 370, 124–130 (2004). https://doi.org/10.1007/s00210-004-0948-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-004-0948-z

Keywords

Search

Navigation