Skip to main content

Advertisement

SpringerLink
Log in

Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers

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

Abstract

Objective

Triflusal has been shown to exert neuroprotective effects by downregulating molecules considered responsible for the development of Alzheimer’s disease (AD). The aim of this study was to develop a population pharmacokinetic model to characterize plasma and cerebrospinal fluid (CSF) pharmacokinetics of the main active metabolite of triflusal—HTB (2-hydroxy-4-trifluoro-methylbenzoic acid)—in healthy volunteers.

Methods

Data from two studies were combined. Study A: subjects received single oral doses of triflusal 900 mg. Triflusal and HTB plasma concentrations were extensively measured. Study B: triflusal 600 mg once daily was administered orally for 14 days. HTB plasma and CSF concentrations were determined in healthy volunteers. Population pharmacokinetic modeling was performed using NONMEM.

Results

A one-compartmental model with rapid first-order absorption for triflusal and first-order formation of HTB best described plasma concentrations. Triflusal elimination rate constant was 50 times faster than that estimated for the metabolite. CSF concentrations of HTB ranged between 0.011 μg/ml and 0.341 μg/ml. A CSF–plasma partition coefficient of 0.002 and a ke0 value of 0.059 h−1 were estimated by means of population modeling.

Conclusion

In the present study in healthy volunteers, HTB penetrated into the CSF in a range of concentrations experimentally proven to have protective effects in AD. These concentrations suggest that triflusal could be used in the treatment of central nervous system diseases in doses similar to those used in cardiovascular diseases. Access to the CSF compartment was characterized by a slow equilibrium rate constant and a low CSF–plasma partition coefficient.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 21(2):195–218

    Article  CAS  PubMed  Google Scholar 

  2. McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47(2):425–432

    Google Scholar 

  3. Mackenzie IR, Hao C, Munoz DG (1995) Role of microglia in senile plaque formation. Neurobiol Aging 16(5):797–804

    Article  Google Scholar 

  4. McNeely W, Goa KL (1998) Triflusal. Drugs 55(6):823–833

    Google Scholar 

  5. García Rafanell J, Planas JM, Puig Parellada P (1979) Comparison of the inhibitory effects of acetylsalicylic and triflusal on enzymes related to thrombosis. Arch Int Pharmacodyn Ther 237(2):343–350

    Google Scholar 

  6. Rutllant Borrel M, Felez J, Diaz JM, Vicente JM, García Rafanell J (1977) Effect of triflusal (UR-1501) a potential antithrombotic agent, on blood coagulation and platelet antiaggregation in man. Curr Ther Res 22:510–521

    Google Scholar 

  7. Domínguez MJ, Vacas H, Saez Y, Olabarria I, Velasco A, Iriarte JA, Forn J (1985) Effects on triflusal with prosthetic heart valves. Clin Ther 7:357–360

    Google Scholar 

  8. De La Cruz JP, Pavía J, Bellido I, González MC, Sánchez de la Cuesta F (1988) Platelet antiaggregator effect of triflusal human whole blood. Methods Find Exp Clin Pharmacol 10(4):273–277

    Google Scholar 

  9. Bucham A (1992) Advances in cerebral ischemia: experimental approaches. Neurol Clin 10:49–61

    Google Scholar 

  10. Fernández de Arriba A, Cavalcanti F, Miralles A, Bayón Y, Alonso M, Merlos M, García-Rafanell J, Forn J (1999) Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid. Mol Pharmacol 4:753–761

    Google Scholar 

  11. Bayón A, Alonso A, Sánchez Crespo M (1999) 4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor B activation. Br J Pharmacol 126:1359–1366

    Google Scholar 

  12. Ramis J, Mis R, Forn J, Torrent J, Gorina E, Jane F (1991) Pharmacokinetics of triflusal and its main metabolite HTB in healthy subjects following a single oral dose. Eur J Drug Metab Pharmacokinet 16(4):269–273

    Google Scholar 

  13. Grasela TH, Sheiner LB (1991) Pharmacostatistical modeling for observational data. J Pharmacokinet Biopharm 19:25S–36S

    Google Scholar 

  14. Beal SL, Sheiner LB (1998) NONMEM users’ guides. NONMEM project group. University of California at San Francisco, San Francisco

  15. Davidian M, Giltinan DM (1995) Non linear models for repeated measurement data. CRC Press, Boca Raton

    Google Scholar 

  16. Sheiner LB, Stanski DR, Vozeh S, Miller R, Ham J (1979) Simultaneous modelling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25:358–371

    Google Scholar 

  17. Jonsson EN, Karlsson MO (1999) Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64

    Google Scholar 

  18. de Lange EC, Danhof M (2002) Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet 41(10):691–703

    Google Scholar 

  19. Acarin L, González B, Castellano B (2001) Triflusal post-treatment inhibits glial nuclear Factor-kB, downregulates the glial response, and is neuroprotective in an exocitotoxic injury model in postnatal brain. Stroke 32:2394–2402

    CAS  PubMed  Google Scholar 

  20. Acarin L, González B, Castellano B (2002) Decrease of proinflammatory molecules correlates with neuroprotective effect of the fluorinated salicylate triflusal after postnatal exocitotoxic damage. Stroke 23:2499–2505

    Article  Google Scholar 

  21. Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajja A, Stewart CF (1996) Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharm 37(3):195–202

    Article  Google Scholar 

  22. Sato S, Kitawa S, Nakajima M, Shimada K, Honda A, Miyazaki H (2001) Assessment of tear concentrations on therapeutic drug monitoring. II. Pharmacokinetic analysis of valproic acid in guinea pig serum, cerebrospinal fluid, and tears. Pharm Res 18(4):500–509

    Article  Google Scholar 

  23. Anderson BJ, Holford NHG, Wollard GA, Chan PLS (1998) Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children. Br J Clin Pharmacol 46:237–243

    Article  Google Scholar 

  24. Rowland M, Tozer TN (1995a) Clinical pharmacokinetics: concepts and applications. Williams & Wilkins, Baltimore, pp 114–116

    Google Scholar 

  25. Rowland M, Tozer TN (1995b) Clinical pharmacokinetics: concepts and applications. Williams & Wilkins, Baltimore, pp 140–142

    Google Scholar 

  26. Tanaka H, Mizojiri K (1999) Drug-protein binding and blood-brain barrier permeability. J Pharmacol Exp Ther 288:912–918

    Google Scholar 

  27. Cruz-Fernández JM, López-Bescos L, García-Dorado D, López-García Aranda V, Cabades A, Martín-Jadraque L, Velasco JA, Castro-Beiras A, Torres F, Marfil F, Navarro E (2000) Randomized comparative trial of triflusal and aspirin following acute myocardial infarction. Eur Heart J 21(6):457–465

    Article  Google Scholar 

  28. Matias-Guiu J, Ferro JM, Alvarez-Sabín J, Torres F, Jiménez MD, Lago A, Melo T, TACIP Investigators (2003) Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction. Stroke 34(4):840–848

    Article  CAS  PubMed  Google Scholar 

  29. Culebras A, Rotta-Escalante R, Vila J, Domínguez R, Abiuisi G, Famulari A, Rey R, Bauso-Toselli L, Gori H, Ferrari J, Reich E, TAPIRSS investigators (2004) Triflusal vs aspirin for prevention of cerebral infarction. A randomized stroke study. Neurology 62:1073–1080

    Google Scholar 

Download references

Acknowledgements

Financial sources of support were provided by J Uriach & Cia, Grupo Uriach (Barcelona, Spain)

Author information

Authors and Affiliations

  1. Centre d’Investigació de Medicaments, Institut de Recerca del HSCSP, Hospital de la Santa Creu i Sant Pau and Departamento de Farmacología y Terapéutica de la Universidad Autónoma de Barcelona, Av Sant Antoni M Claret 167, 08025, Barcelona, Spain

    M. Valle & M. J. Barbanoj

  2. Department of Anesthesiology and Intensive Care, University of Vienna Medical School, Vienna, Austria

    A. Donner

  3. Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, University of Vienna Medical School, Vienna, Austria

    N. Klein, H. G. Eichler, M. Müller & M. Brunner

  4. Clinical Research Unit J. Uriach & CIA S.A, Barcelona, Spain

    I. Izquierdo

  5. CROSS s.a., Arzo, Switzerland

    U. Herranz

Authors
  1. M. Valle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. J. Barbanoj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Donner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U. Herranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. G. Eichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Brunner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Valle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Valle, M., Barbanoj, M.J., Donner, A. et al. Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers. Eur J Clin Pharmacol 61, 103–111 (2005). https://doi.org/10.1007/s00228-004-0887-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-004-0887-0

Keywords

Search

Navigation