Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study

  • Jurij Zdovc
  • Maja Petre
  • Mitja Pišlar
  • Katja Repnik
  • Aleš Mrhar
  • Matjaž Vogrin
  • Uroš Potočnik
  • Iztok GrabnarEmail author
Pharmacokinetics and Disposition



Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects.


Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects.


A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration.


We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.


Rivaroxaban Population pharmacokinetics/pharmacodynamics ABCB1 expression Orthopedic surgery 


Author contributions

MPe, AM, MV, UP, and IG conceived and designed the study. MV recruited the patients and was the principal clinical investigator. MPe, KR, and UP performed the biochemical and genetic analyses. JZ, MPi, and IG analyzed the data. JZ and IG drafted the first manuscript. UP and AM provided scientific supervision. All authors reviewed and approved the final manuscript.

Funding information

This work was financially supported by the Slovenian Research Agency (ARRS Grants P1-0189 and P3-0067).

Compliance with ethical standards

The study was conducted in accordance with the Helsinki declaration and was approved by the National Medical Ethics Committee of the Republic of Slovenia (168/07/11). Written informed consent was obtained from all patients prior to inclusion in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2019_2639_MOESM1_ESM.docx (2.9 mb)
ESM 1 (DOCX 2944 kb)


  1. 1.
    Agnelli G (2004) Prevention of venous thromboembolism in surgical patients. Circulation 110:4–13. CrossRefGoogle Scholar
  2. 2.
    Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW (2008) Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133:381S–453S. CrossRefGoogle Scholar
  3. 3.
    Gillespie W, Murray D, Gregg PJ, Warwick D (2000) Risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 82:475–479. CrossRefGoogle Scholar
  4. 4.
    Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar AK, Kälebo P, Kwong LM, Misselwitz F, Turpie AGG (2008) Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 47:203–216. CrossRefGoogle Scholar
  5. 5.
    Duggan ST (2012) Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery. Am J Cardiovasc Drugs 12:57–72. CrossRefGoogle Scholar
  6. 6.
    Antoniou S (2015) Rivaroxaban for the treatment and prevention of thromboembolic disease. J Pharm Pharmacol 67:1119–1132. CrossRefGoogle Scholar
  7. 7.
    Frostick S (2016) Pharmacological thromboprophylaxis and total hip or knee replacement. Br J Nurs 25:45–53. CrossRefGoogle Scholar
  8. 8.
    Friedman RJ (2010) New oral anticoagulants for thromboprophylaxis after elective total hip and knee arthroplasty. Thrombosis 2010:280731. Google Scholar
  9. 9.
    Stampfuss J, Kubitza D, Becka M, Mueck W (2013) The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 51:549–561. CrossRefGoogle Scholar
  10. 10.
    (2016) Janssen Pharmaceuticals XareltoGoogle Scholar
  11. 11.
    Kubitza D, Becka M, Voith B et al (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78:412–421. CrossRefGoogle Scholar
  12. 12.
    Mueck W, Stampfuss J, Kubitza D, Becka M (2014) Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 53:1–16. CrossRefGoogle Scholar
  13. 13.
    Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37:1056–1064. CrossRefGoogle Scholar
  14. 14.
    Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S (2011) In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338:372–380. CrossRefGoogle Scholar
  15. 15.
    Mueck W, Kubitza D, Becka M (2013) Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 76:455–466. CrossRefGoogle Scholar
  16. 16.
    Gong IY, Mansell SE, Kim RB (2013) Absence of both MDR1 (ABCB1) and breast cancer resistance protein (ABCG2) transporters significantly alters rivaroxaban disposition and central nervous system entry. Basic Clin Pharmacol Toxicol 112:164–170. CrossRefGoogle Scholar
  17. 17.
    Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 21:152–161. CrossRefGoogle Scholar
  18. 18.
    Hodin S, Basset T, Jacqueroux E, Delezay O (2017) In vitro comparison of the role of P-glycoprotein and breast cancer resistance protein on direct oral anticoagulants disposition. Eur J Drug Metab Pharmacokinet 43:183–191. CrossRefGoogle Scholar
  19. 19.
    Lorenzini KI, Daali Y, Fontana P et al (2016) Rivaroxaban-induced hemorrhage associated with ABCB1 genetic defect. Front Pharmacol 7:1–5. Google Scholar
  20. 20.
    Gouin-Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C, Gaussem P, Beaune P, Funck-Brentano C, Azizi M, Mismetti P, Loriot MA (2017) Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost 15:273–283. CrossRefGoogle Scholar
  21. 21.
    Sennesael A, Panin N, Vancraeynest C et al (2018) Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines. Sci Rep 8:6–11. CrossRefGoogle Scholar
  22. 22.
    Sennesael A, Larock A, Douxfils J et al (2018) Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb J 16:1–8. CrossRefGoogle Scholar
  23. 23.
    Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M (2007) Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa - inhibitor in healthy subjects. Int J Clin Pharmacol Ther 45:335–344. CrossRefGoogle Scholar
  24. 24.
    Mueck W, Borris LC, Dahl OE et al (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100:453–461. CrossRefGoogle Scholar
  25. 25.
    Mueck W, Lensing AWA, Agnelli G, Decousus H, Prandoni P, Misselwitz F (2011) Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 50:675–686. CrossRefGoogle Scholar
  26. 26.
    Girgis IG, Patel MR, Peters GR, et al (2014) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.
  27. 27.
    Xu XS, Moore K, Burton P, Stuyckens K, Mueck W, Rossenu S, Plotnikov A, Gibson M, Vermeulen A (2012) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol 74:86–97. CrossRefGoogle Scholar
  28. 28.
    Willmann S, Zhang L, Frede M, Kubitza D, Mueck W, Schmidt S, Solms A, Yan X, Garmann D (2018) Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations. CPT Pharmacometrics Syst Pharmacol 7:309–320. CrossRefGoogle Scholar
  29. 29.
    Levey A, Green T, Kusek J, Beck G (2000) MDRD Study Group. A simplified equation to predict glomerular filtration rate from serum creatinine (abstract). J Am Soc Nephrol 11:155A (A0828)Google Scholar
  30. 30.
    Douxfils J, Tamigniau A, Chatelain B, Chatelain C, Wallemacq P, Dogné JM, Mullier F (2013) Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 110:723–731. CrossRefGoogle Scholar
  31. 31.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and. Methods 25:402–408. CrossRefGoogle Scholar
  32. 32.
    Sudchada P, Oo-Puthinan S, Kerdpin O, Saelim N (2010) ABCB1 gene expression in peripheral blood mononuclear cells in healthy Thai males and females. Genet Mol Res 9:1177–1185. CrossRefGoogle Scholar
  33. 33.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2009) NONMEM user’s guides. (1989–2009). Ellicott City, MD, USAGoogle Scholar
  34. 34.
    Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11:371–380. CrossRefGoogle Scholar
  35. 35.
    Hegarty JP, Sangster W, Harris LR, Stewart DB (2014) Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection. Surgery 156:972–978. CrossRefGoogle Scholar
  36. 36.
    Rekersbrink CPS, Klotz U, Fromm MF (2001) Interaction of omeprazole , lansoprazole and pantoprazole with P-glycoprotein. 551–557.
  37. 37.
    Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P, Siegbahn A, Syvanen AC, Wadelius C, Wadelius M, Zimdahl-Gelling H, Yusuf S, Wallentin L (2013) Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127:1404–1412. CrossRefGoogle Scholar
  38. 38.
    Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV, Loskutnikov MA, Smirnov VV, Konova OD, Matsneva IA, Bochkov PO (2018) Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharmgenomics Pers Med 11:43–49. Google Scholar
  39. 39.
    Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Horie M, Terada T, Katsura T (2017) Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics 27:329–336. CrossRefGoogle Scholar
  40. 40.
    Eikelboom JW, Quinlan DJ, Hirsh J, et al (2017) Laboratory monitoring of non–vitamin K antagonist oral anticoagulant use in patients with atrial fibrillation: a review. 1–9 . doi:
  41. 41.
    Freyburger G, Macouillard G, Labrouche S, Sztark F (2011) Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 127:457–465. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.University Medical Centre MariborMariborSlovenia
  3. 3.Faculty of MedicineUniversity of MariborMariborSlovenia
  4. 4.Faculty for Chemistry and Chemical EngineeringUniversity of MariborMariborSlovenia

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