Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine

The in vitro uptake of 5-methyltetrahydrofolate (5-MeTHF) by rat and human intestine is dose-dependently inhibited by the antidepressant drug fluoxeti ne (FLX). In rat jejunum rings, 0.2 rnM FLX inhibited the uptake of 5-MeTHF (0.25 muM) by 32% (15 min) and 49% (45 min). In brush border membrane vesi cles (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 pass ive diffusion component becomes prominent by high substrate concentration, or by 0-4 degreesC incubation or by addition of the folate transport inhibi tor DIDS (1 mM). The kinetic analysis with rat BBMV suggests a non-competit ive inhibition of the 5-MeTHF transport by FLX, with apparent values for K- M = 0.89 muM, Vmax = 1.89 pmol/mg prot./10 s, and K-I = 0.21 mM. After 21 d ays of treatment with FLX (10 mg/kg/day), the folate uptake by jejunum ring s or by BBMV from the treated rats was diminished, and the folate levels in erythrocytes and serum were also decreased.