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Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine

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

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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.

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Authors and Affiliations

  1. Depto. de Fisiología y Nutrición, Facultad de Farmacia, Universidad de Navarra, Navarra, Spain

    A. Amilburu, F. Ponz & J. Larralde

  2. Departamento de Bioquímica, Hospital Virgen del Camino, Pamplona, Spain

    I. Idoate

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  1. A. Amilburu
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  2. I. Idoate
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  3. F. Ponz
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  4. J. Larralde
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Correspondence to F. Ponz.

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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

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  • DOI: https://doi.org/10.1007/BF03179072

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