Skip to main content
Log in

Fondaparinux Sodium Is Not Metabolised in Mammalian Liver Fractions and Does Not Inhibit Cytochrome P450-Mediated Metabolism of Concomitant Drugs

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objective: To investigate the in vitro metabolism of the antithrombotic agent fondaparinux sodium in mammalian liver fractions and to evaluate its potential inhibitory effect on human cytochrome P450 (CYP)-mediated metabolism of other drugs.

Methods: Metabolism was evaluated by incubating radioisotope-labelled fondaparinux sodium with postmitochondrial liver fractions of rat, rabbit, monkey or human origin (three subjects). Human liver microsomal preparations and an NADPH-generating system were incubated with phenacetin, coumarin, tolbutamide, S-mephenytoin, bufuralol, chlorzoxazone or nifedipine. These are selectively metabolised by CYP isoforms: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, respectively. Experiments were designed to determine apparent Ki (inhibitory constant) values for fondaparinux sodium against each CYP isoform, by varying concentrations of fondaparinux sodium and the selective substrate. Each experiment included control reaction mixtures containing an isoform-selective inhibitor. After incubation, the mixtures were analysed by LC-MS/MS or with fluorometric detection.

Results: All liver fractions were enzymatically active, as demonstrated by degradation of [14C]testosterone. No metabolism of fondaparinux sodium was detectable in postmitochondrial liver fractions. Apparent Ki values for fondaparinux sodium against the CYP isoforms could not be determined because the oxidative metabolism of the isoform-selective CYP substrates was not significantly inhibited in pooled microsomal reaction mixtures. In the presence of selective CYP inhibitors, metabolism of each substrate was significantly reduced, confirming that inhibition could be observed in these assays.

Conclusion: The demonstrated lack of mammalian hepatic metabolism of fondaparinux sodium is consistent with animal and human studies. The absence of inhibition of the human CYP isoforms commonly involved in the metabolism of drugs suggests that clinical treatment with fondaparinux sodium is unlikely to interfere with the pharmacokinetics and metabolism of a wide range of other drugs which are associated with CYP inhibition.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Fig. 1

Similar content being viewed by others

References

  1. Boneu B. New antithrombotic agents for the prevention and treatment of deep vein thrombosis. Haemostasis 1996; 26 Suppl. 4: 368–78

    PubMed  CAS  Google Scholar 

  2. Lormeau JC, Herault JP, Gaich C, et al. Determination of the anti-factor Xa activity of the synthetic pentasaccharide SR90107A/ORG 31540 and of two structural analogues. Thromb Res 1997; 85: 67–75

    Article  PubMed  CAS  Google Scholar 

  3. Walenga JM, Jeske WP, Bara L, et al. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997; 86: 1–36

    Article  PubMed  CAS  Google Scholar 

  4. Casu B. Structure and biological activity of heparin. Adv Carbohydr Chem Biochem 1985; 43: 51–134

    Article  PubMed  CAS  Google Scholar 

  5. Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 1992; 22: 359–74

    Article  PubMed  CAS  Google Scholar 

  6. Mammen EF. Low molecular weight heparins and heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 1999; 5 Suppl. 1: S72–5

    Article  PubMed  Google Scholar 

  7. Fabris F, Luzzatto G, Stefani PM, et al. Heparin-induced thrombocytopenia. Haematologica 2000; 85: 72–81

    PubMed  CAS  Google Scholar 

  8. Fareed J, Hoppensteadt DA, Bick RL. An update on heparins at the beginning of the new millennium. Semin Thromb Hemost 2000; 26 Suppl. 1: 5–21

    Article  PubMed  CAS  Google Scholar 

  9. Turpie AG, Gallus AS, Hoek JA and the Pentasaccharide Investigators, et al. A synthetic pentasaccharide for the prevention of deep vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619–25

    Article  PubMed  CAS  Google Scholar 

  10. Lassen MR, Bauer KA, Eriksson BI, et al. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in elective hip replacement surgery: a randomized double-blind comparison. Lancet 2002; 359: 1715–20

    Article  PubMed  CAS  Google Scholar 

  11. Turpie AGG, Bauer KA, Eriksson BI, et al. A randomized double-blind comparison of fondaparinux with enoxaparin for the prevention of venous thromboembolism after elective hip replacement surgery. Lancet 2002; 359: 1721–6

    Article  PubMed  CAS  Google Scholar 

  12. Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298–304

    Article  PubMed  CAS  Google Scholar 

  13. Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305–10

    Article  PubMed  CAS  Google Scholar 

  14. Murray M, Reidy GF. Selectivity in the inhibition of mammalian cytochromes P450 by chemical agents. Pharmacol Rev 1990; 42: 85–101

    PubMed  CAS  Google Scholar 

  15. Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992; 13: 434–9

    Article  PubMed  CAS  Google Scholar 

  16. Guengerich FP. Catalytic selectivity of human cytochrome P450: relevance to drug metabolism and toxicity. Toxicol Lett 1994; 70: 133–8

    Article  PubMed  CAS  Google Scholar 

  17. Omura T, Sato R. The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 1964; 239: 2370–8

    PubMed  CAS  Google Scholar 

  18. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265–75

    PubMed  CAS  Google Scholar 

  19. Shah VP, Midha KK, Findlay JWA, et al. Bioanalytical method validation: a revisit with a decade of progress. Pharm Res 2000; 17: 1551–7

    Article  PubMed  CAS  Google Scholar 

  20. Herbert JM, Petitou M, Lormeau JC, et al. SR90107A/Org 31540, a novel anti-factor Xa antithrombotic agent. Car-diovasc Drug Rev 1997; 15: 1–26

    Article  CAS  Google Scholar 

  21. Wells XE, Dawes J. Role of the liver and kidney in the desulphation of heparin in vivo. Thromb Haemost 1995; 74: 667–72

    PubMed  CAS  Google Scholar 

  22. Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 Suppl. 2: 24–38

    PubMed  CAS  Google Scholar 

  23. Santoni A, Duvauchelle T. Safety and pharmacokinetics of co-administration of the first synthetic factor Xa inhibitor and aspirin in human volunteers [abstract no. 226]. The 42nd Annual Meeting of the American Society of Hematology; 2000 Dec 1–5; San Francisco

    Google Scholar 

  24. Faaij RA, Burggraaf J, Cohen AM. Lack of pharmacokinetic (PK) and pharmacodynamic (PD) interaction between the first synthetic factor Xa inhibitor and warfarin in human volunteers [abstract no. 234]. The 42nd Annual Meeting of the American Society of Hematology; 2000 Dec 1–5; San Francisco

    Google Scholar 

  25. Ollier C, Santoni A, Faaij RA, et al. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clin Pharmacokinet 2002; 41 Suppl. 2: 31–37

    Article  PubMed  CAS  Google Scholar 

  26. Faaij RA, Burggraaf J, Schoemaker RC, et al. The synthetic pentasaccharide fondaparinux sodium does not interact with oral warfarin (Short Communication). Clin Pharmacokinet 2002; 41 Suppl. 2: 27–29

    Article  PubMed  Google Scholar 

  27. Mant T, Fournié P, Ollier C, et al. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl. 2: 39–45

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to François Donat.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lieu, C., Shi, J., Donat, F. et al. Fondaparinux Sodium Is Not Metabolised in Mammalian Liver Fractions and Does Not Inhibit Cytochrome P450-Mediated Metabolism of Concomitant Drugs. Clin Pharmacokinet 41 (Suppl 2), 19–26 (2002). https://doi.org/10.2165/00003088-200241002-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200241002-00003

Keywords

Navigation