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Basolateral Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) Facilitates Intestinal Absorption of Folates in Mouse

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Abstract

Purpose

This study investigated the role of an ABC transporter, Mrp3/Abcc3 in intestinal folate absorption.

Methods

Plasma concentrations of folic acid and leucovorin, given orally, were determined in wild-type and Mrp3 −/− mice. Mucosal-to-serosal transport was determined in the everted intestinal sacs. The plasma concentrations of endogenous 5-methyltetrahydrofolic acid, homocysteine and vitamin B12, and mRNA levels of hepatic and intestinal folate metabolizing enzymes were compared between wild-type and Mrp3 −/− mice.

Results

C max and area-under plasma concentration–time curve of folic acid were 3.0- and 2.3-fold lower in Mrp3−/− mice compared with wild-type mice, whereas the total body clearance was unchanged. Absorption of leucovorin was significantly delayed in Mrp3−/− mice. Mucosal-to-serosal transport of folic acid and leucovorin was significantly decreased in the duodenum of Mrp3−/− mice, where their PS serosal was decreased to 6.3 and 22% of that in wild-type mice, respectively. PS serosal of 5-methyltetrahydrofolic acid was moderately decreased in Mrp3−/− mice. There was no obvious abnormality in folate homeostasis in Mrp3−/− mice.

Conclusions

Mrp3 accounts for the serosal efflux of folic acid and leucovorin, while it makes a moderate contribution to the serosal efflux of 5-methyltetrahydrofolic acid in mice. Mrp3 dysfunction does not disrupt folate homeostasis in mouse.

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Abbreviations

5MeTHF:

5-methyltetrahydrofolic acid

ABC:

ATP-binding cassette

BLMV:

basolateral membrane vesicle

BCRP:

breast cancer resistance protein

LC/MS/MS:

liquid chromatography/tandem mass spectrometry

MRP:

multidrug resistance-associated protein

PCFT:

proton-coupled folate transporter

RFC:

reduced folate carrier

THF:

tetrahydrofolic acid

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Acknowledgments

We would like to thank Dr. Piet Borst (The Netherlands Cancer Institute, Amsterdam, The Netherlands) for supplying the Mrp3 −/− mice. This work was supported by Grant-in-Aid for Scientific Research (A) (20249008) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yoshiaki Kitamura, Hiroyuki Kusuhara & Yuichi Sugiyama

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  1. Yoshiaki Kitamura
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  2. Hiroyuki Kusuhara
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  3. Yuichi Sugiyama
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Correspondence to Yuichi Sugiyama.

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Kitamura, Y., Kusuhara, H. & Sugiyama, Y. Basolateral Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) Facilitates Intestinal Absorption of Folates in Mouse. Pharm Res 27, 665–672 (2010). https://doi.org/10.1007/s11095-009-0047-4

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