Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine

Inhibición de la absorción intestinal de 5-metil-tetrahidrofolato por la fluoxetina

Abstract

Thein vitro uptake of 5-methyltetrahydrofolate (5-MeTHF) by rat and human intestine is dose-dependently inhibited by the antidepressant drug fluoxetine (FLX). In rat jejunum rings, 0.2 mM FLX inhibited the uptake of 5-MeTHF (0.25 μM) by 32% (15 min) and 49% (45 min). In brush border membrane vesicles (BBMV) from rat jejunum, 0.2 mM FLX inhibited the folate uptake at the overshoot (90 s) by 40 %. Similar inhibition was observed with human Caco-2 cells and duodenal biopsies. FLX action is exerted on the active transport component of the folate uptake, since the drug has no effect when the passive diffusion component becomes prominent by high substrate concentration, or by 0-4 ºC incubation or by addition of the folate transport inhibitor DIDS (1mM). The kinetic analysis with rat BBMV suggests a non-competitive inhibition of the 5-MeTHF transport by FLX, with apparent values for KM = 0.89 μM, Vmax = 1.89 pmol/mg prot./10 s, and KI = 0.21 mM. After 21 days of treatment with FLX (10 mg/kg/day), the folate uptake by jejunum rings or by BBMV from the treated rats was diminished, and the folate levels in erythrocytes and serum were also decreased.

Resumen

La entrada de 5-metil-tetrahidrofolato (5-MeTHF) a los enterocitos de intestino de rata y de humanos in vitro se inhibe por el antidepresivo fluoxetina (FLX) a concentraciones 0,1 mM y superiores. En anillos de yeyuno de rata, FLX 0.2 mM inhibe la entrada de 5-MeTHF (0,25 mM) un 32 % (15 min) y un 49 % (45 min). En vesículas de membrana del borde en cepillo (BBMV) de yeyuno de rata, FLX 0,2mM inhibe un 40 % la incorporación de 5-MeTHF (0,25 mM) en el pico máximo (90 s). Con células humanas Caco-2 y con biopsias duodenales se observaron inhibiciones parecidas. La acción de la FLX se ejerce sobre el componente de transporte activo de la entrada de folato, ya que el fármaco carece de efecto cuando el componente de difusián pasiva se hace muy prominente por alta concentración de substrato, por incubación a 0-4 ºC, o por adición de DIDS 1mM que inhibe el transporte del folato. El análisis cinético con BBMV de rata sugiere que la inhibición del transporte de 5-MeTHF por FLX es de tipo no competitivo, con valores aparentes de KM = 0,89 μM, Vmax = 1,89 pmol/mg prot./10 s, y KI = 0,21 mM. Después de un tratamiento de 21 días con FLX (10 mg/kg/día), la incorporación de folato por anillos de yeyuno o por BBMV de las ratas tratadas está disminuida y los niveles de folato en eritrocitos y suero son también menores.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Altamura, A. C., Moro, A. R., Percudani, M. (1994):Clin. Pharmacokinet.,26, 201–214.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Beasley, C. M., Masica, D, N. and Potvin, J. H. (1992):Psychopharm. Berl.,107, 1–10.

    Article  CAS  Google Scholar 

  3. 3.

    Bradford, B. B. (1976):Anal. Biochem.,72, 248–254.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Butteworth, C. E., Santini, R. and Frommeyer, W. B. (1963):J. Clin. Invest.,42, 1929–1939.

    Article  Google Scholar 

  5. 5.

    Chandler, C. J., Wang, T.T. and Halsted, C. H. (1986):J. Biol. Chem.,261, 928–933.

    CAS  PubMed  Google Scholar 

  6. 6.

    Crane, R. K. and Maldestan, P. (1960):Biochim. Biophys. Acta,45, 460–467.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Dahlqvist, A. (1984):Anal. Biochem.,7, 18–25.

    Article  Google Scholar 

  8. 8.

    Dhar, G. H., Selhub, J., Gay, C. and Rosenberg, I. H. (1977):Gastroenterology,72, 1049.

    Google Scholar 

  9. 9.

    Durand, P., Prost, M., Blache, D. (1997):Arterioscler. Thromb. Vasc. Biol.,17, 1939–1946.

    CAS  PubMed  Google Scholar 

  10. 10.

    Durand, P, Prost, M., Blache, D. (1998):Clin. Chem. Lab. Med.,36, 419–429.

    Article  PubMed  Google Scholar 

  11. 11.

    Eli Lilly and Co.,Fluoxetine prescribing information, (1994), Indianapolis.

  12. 12.

    Elsborg, L., Lyngbye, J. and Rittig, K. (1981): In “Folic acid and folic acid deficiency”, A/S Ferrosan, Copenhagen.

    Google Scholar 

  13. 13.

    Fava, M., Borus, J. S., Alpert, J. E., Nierenberg, A. A., Rosenbaum, J. F., Bottiglieri, T. (1997):Am. J. Psychiatry,154, 426–428.

    CAS  PubMed  Google Scholar 

  14. 14.

    Gan, L. S., Hsyu, P. H., Pritchard, J. F., Thakker, D. (1993):Pharm. Res.,10, 1722–1725.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Goodman and Gilman. (1996): In “Las bases farmacológicas de la terapéutica”, Interamericana, Madrid.

    Google Scholar 

  16. 16.

    Hall, H. M., Pirini, B. B. K. and Campbell, D. (1976):Br. J. Obstet. Gynaecol.,83, 132.

    CAS  PubMed  Google Scholar 

  17. 17.

    Halsted, C. H. (1990): In “Folic acid metabolism in health and disease” (Picciano, M. F., Stockstad, E. L. R. and Gegory, J. F., eds.), Wiley-Lyss, New York, pp. 23–45.

    Google Scholar 

  18. 18.

    Hopfer, U., Nelson, K., Perrotto, J. and Isselbacher, K. J. (1973):J. Biol. Chem.,248, 25–32.

    CAS  PubMed  Google Scholar 

  19. 19.

    Jorgensen, P. L. (1975):Biochim. Biophys. Acta,401, 399–415.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Kumar, C. K., Moyer, M. P., Dudeja, P. K. and Said, H. M. (1997):J. Biol. Chem.,272, 6226–6231.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Kumar, C. K., Nguyen, T. T., Gonz’alez, F.B. and Said, H. M. (1998):Am. J. Physiol.,274, 289–294.

    Google Scholar 

  22. 22.

    Mason, J. B. (1990): In “Folic acid metabolism in health and disease” (Picciano, M. F., Stockstad, E. L. R. and Gregory, J. F. eds.), Wiley-Lyss, New York, pp. 47–54.

    Google Scholar 

  23. 23.

    Monteiro, J. B. R., Jordan, J., Barber, A. y Larralde, J. (1993):J. Clin. Nutr. Gastroenterology,8, 13–20.

    CAS  Google Scholar 

  24. 24.

    Nguyen, T.T., Dyer, D. L., Dunning D.D., Rubin, S. A., Grant, K, E, Said, H. M. (1997):Gastroenteroloy,112, 783–791.

    Article  CAS  Google Scholar 

  25. 25.

    Pinto, M., Robine-León, S., Appay, M. D., Kedinger, M., Triadou, N., Dussaulx, E., Lacroix, B., Simmon-Assmann, P., Haffen, K., Fogh, J., Zweibaum, A. (1983):Biol. Cell.,47, 323–330.

    Google Scholar 

  26. 26.

    Rosalki, S. B., Foo, A. Y., Burlina, A., Prellwitz, W., Stieber, P., Neumeier, D., Klein, G., Poppe, W. A. and Bodenmuller, H. (1993):Clin. Chem.,39, 648–652.

    CAS  PubMed  Google Scholar 

  27. 27.

    Rosenberg, I. H. (1981): In “Physiology of gastrointestinal tract” (Johnson, L., ed.), Raven Press, New York, pp. 1221–1230.

    Google Scholar 

  28. 28.

    Said, H. M., Ghisan, F. K., Murrell, J. E. (1985):Am. J. Physiol.,249, 567–571.

    Google Scholar 

  29. 29.

    Said, H. M., Ghishan, F. K. and Redha, R. (1987):Am. J. Physiol.,252, G229-G236.

    CAS  PubMed  Google Scholar 

  30. 30.

    Said, H. M., Nguyen, T. T., Dyer, D. L., Cowan, K. H. and Rubin, S. A. (1996):Biochim. Biophys. Acta,1281, 164–172.

    Article  PubMed  Google Scholar 

  31. 31.

    Said, H. M., Ortiz, A., Tapia, A. and Valerio, C. K. (1997):Am. J. Physiol.,272, 729–736.

    Google Scholar 

  32. 32.

    Said, H. M. and Redha, R. (1987):Biochem. J.,247, 141–146.

    CAS  PubMed  Google Scholar 

  33. 33.

    Said, H. M. and Strum, W. B. (1983):J. Pharmacol. Exp. Ther.,226, 95–99.

    CAS  PubMed  Google Scholar 

  34. 34.

    Schron, C. M., Washington, C. and Blitzer, B. L. (1985):J. Clin. Invest.,76, 2030–2033.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Selhub, J. and Rosenberg, I. H (1981):J. Biol. Chem.,256, 4489–4493.

    CAS  PubMed  Google Scholar 

  36. 36.

    Shirazi-Beechey, S. P., Davies, A. G. and Tebutt, K. (1990):Gastroenterology,98, 676–685.

    CAS  PubMed  Google Scholar 

  37. 37.

    Torania, S. A., Naom, H. F., Said, H. M. and Dudeja, P. K. (1995):Gastroenterology,108, 757.

    Article  Google Scholar 

  38. 38.

    Urdaneta, E., Idoate, I. and Larralde, J. (1998):Br. J. Nutr.,79, 439–446.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Van den Berg, H., Finglas, P. M. and Bates, C. (1994):Int. J. Vit. Nutr. Res.,64, 288–293.

    Google Scholar 

  40. 40.

    Webster, S. G. P. and Leaning, J. T. (1979):J. Am. Geriatr. Soc.,27, 451–454.

    CAS  PubMed  Google Scholar 

  41. 41.

    Wong, D. T., Bymaster, F.P. and Engleman, E. A. (1995):Life Sci.,57, 411–441.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Zimmerman, J. (1990):Gastroenterology,99, 964–972.

    CAS  PubMed  Google Scholar 

  43. 43.

    Zimmerman, J. (1992):Biochem. Pharmacol.,44, 1839–1842.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to F. Ponz.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Amilburu, A., Idoate, I., Ponz, F. et al. Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine. J Physiol Biochem 57, 71–79 (2001). https://doi.org/10.1007/BF03179072

Download citation

Key words

  • Folate
  • Intestinal absorption
  • Fluoxetine

Palabras clave

  • Folato
  • Absorción intestinal
  • Fluoxetina