Skip to main content

Advertisement

SpringerLink
Log in

The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL.

Methods

The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5–15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5–3 g daily, n=81).

Results

The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66–13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58–6.87).

Conclusion

The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.

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

Similar content being viewed by others

References

  1. Chan ES, Cronstein BN (2002) Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4:266–273

    Article  PubMed  Google Scholar 

  2. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesmann MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84:265–269

    Article  PubMed  CAS  Google Scholar 

  3. Lum BL, Gosland MP (1995) MDR expression in normal tissues: pharmacological implications for the clinical use of the P-glycoprotein inhibitors. Hematol Oncol Clin North Am 9:319–336

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. Klimecki WT, Futscher BW, Grogan TM, Dalton WS (1994) P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 83:2451–2458

    PubMed  CAS  Google Scholar 

  6. Marie JP (1995) P-glycoprotein in adult hematologic malignances. Hematol Oncol Clin North Am 9:239–249

    PubMed  CAS  Google Scholar 

  7. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478

    Article  PubMed  CAS  Google Scholar 

  8. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199

    Article  PubMed  CAS  Google Scholar 

  9. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y et al (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143

    PubMed  CAS  Google Scholar 

  10. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15:693–704

    Article  PubMed  CAS  Google Scholar 

  11. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V (1995) American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727–735

    PubMed  CAS  Google Scholar 

  12. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B et al (1993) The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum 36:729–740

    PubMed  CAS  Google Scholar 

  13. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69:169–174

    Article  PubMed  CAS  Google Scholar 

  14. Yudoh K, Matsuno H, Nakazawa F, Yonezawa T, Kimura T (1999) Increased expression of multidrug resistance of P-glycoprotein on Th1 cells correlates with drug resistance in rheumatoid arthritis. Arthritis Rheum 42:2014–2015

    Article  PubMed  CAS  Google Scholar 

  15. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska-Szklarz B (2004) The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther 42:496–503

    PubMed  CAS  Google Scholar 

  16. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P (1995) Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96:1698–1705

    PubMed  CAS  Google Scholar 

  17. Bourgeois SD, Gruol J, Newby RF, Rajah FM, Bourgeois S, Gruol DJ et al (1993) Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis. Mol Endocrinol 7:840–851

    Article  PubMed  CAS  Google Scholar 

  18. Fardel O, Lecureur V, Guillouzo A (1993) Regulation by dexamethasone of P-glycoprotein expression in cultured rat hepatocytes. FEBS Lett 327:189–193

    Article  PubMed  CAS  Google Scholar 

  19. Saitoh H, Hatakeyama M, Eguchi O, Oda M, Takada M (1998) Involvement of intestinal P-glycoprotein in the restricted absorption of methylprednisolone from rat small intestine. J Pharm Sci 87:73–75

    Article  PubMed  CAS  Google Scholar 

  20. Nelson EJ, Hinkle PM (1992) Characterization of multidrug-resistant pituitary tumor cells. Endocrinology 130:3246–3256

    Article  PubMed  CAS  Google Scholar 

  21. Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J (1996) Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer 65:613–619

    Article  PubMed  CAS  Google Scholar 

  22. Graaf D, Sharma RC, Mechetner EB, Schimke RT, Roninson IB (1996) P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc Natl Acad Sci USA 93:1238–1242

    Article  PubMed  Google Scholar 

  23. Mols R, Deferme S, Augustijns P (2005) Sulfasalazine transport in in-vitro, ex-vivo and in-vivo absorbtion models: contribution of efflux carriers and their modulation by co-administration of synthetic nature-identical fruit extracts. J Pharm Pharmacol 57:1565–1573

    Article  PubMed  CAS  Google Scholar 

  24. Llorente L, Richaud-Patin Y, Diaz-Borjon A, Alvarado de la Barrera C, Jakez-Ocampo J, de la Fuente H et al (2000) Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I: Increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Joint Bone Spine 67:30–39

    PubMed  CAS  Google Scholar 

  25. Raghu G, Park SW, Roninson IB, Mechetner EB (1996) Monoclonal antibodies against P-glycoprotein an MDR1 gene product, inhibit interleukin-2 release from PHA-activated lymphocytes. Exp Hematol 24:1258–1264

    PubMed  CAS  Google Scholar 

  26. Drach J, Gsur A, Hamilton G, Zhao S, Angerler J, Fiegl M et al (1996) Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes. Blood 88:1747–1754

    PubMed  CAS  Google Scholar 

  27. Pawlik A, Baskiewicz-Masiuk M, Machalinski B, Safranow K, Gawronska-Szklarz B (2005) Involvement of P-glycoprotein in the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. J Pharm Pharmacol 57:1421–1425

    Article  PubMed  CAS  Google Scholar 

  28. Pawlik A, Baskiewicz-Masiuk M, Machalinski B, Kurzawski M, Gawronska-Szklarz B (2005) Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. Eur J Pharmacol 528:27–36

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The study was supported by grant 2P05B11029 for the years 2005–2008 from the Ministry of Education and Science (Warsaw, Poland).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Pomeranian Medical University, ul. Powstancow Wlkp. 72, 70-111, Szczecin, Poland

    Marek Drozdzik, Tomasz Rudas, Andrzej Pawlik, Mateusz Kurzawski, Bogusław Czerny & Wanda Gornik

  2. Department of Rheumatology, County Hospital, Szczecin, Poland

    Magdalena Herczynska

Authors
  1. Marek Drozdzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomasz Rudas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrzej Pawlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mateusz Kurzawski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bogusław Czerny
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wanda Gornik
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Magdalena Herczynska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrzej Pawlik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drozdzik, M., Rudas, T., Pawlik, A. et al. The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur J Clin Pharmacol 62, 933–937 (2006). https://doi.org/10.1007/s00228-006-0192-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-006-0192-1

Keywords

Search

Navigation