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Involvement of Organic Anion Transporting Polypeptide 1a5 (Oatp1a5) in the Intestinal Absorption of Endothelin Receptor Antagonist in Rats

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Abstract

Purpose

To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats.

Methods

Uptakes of [14C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated.

Results

The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K m value of 116 μM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K m value was 83 μM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid.

Conclusions

These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats.

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Abbreviations

BSP:

bromosulfophthalein

Caco-2:

human colon carcinoma cell line

cRNA:

complementary ribonucleic acid

ET:

endothelin

HEPES:

N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

K m :

Michaelis–Menten constant

k ns :

nonsaturable uptake clearance

LLC-PK1:

porcine kidney epithelial cell

MES:

2-N-morpholinoethanesulfonic acid

OATP/Oatp:

organic anion transporting polypeptide

TCA:

taurocholic acid

V max :

maximum uptake rate

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Acknowledgements

The Drug Research Academy at University of Copenhagen are acknowledged for financial support, as well as Brorsons travelfund and OTICON foundation are acknowledged for funding external tuition fee and hence enable the collaboration behind this study.

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Authors and Affiliations

  1. Drug Metabolism, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan

    Takeshi Tani, Masato Chiba & Yasuyuki Ishii

  2. Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamasaki, Noda, Chiba, 278-8510, Japan

    Luise K. Gram, Hiroshi Arakawa, Akihiro Kikuchi & Ikumi Tamai

  3. Molecular Biopharmaceutics, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, Dk-2100, Copenhagen, Denmark

    Luise K. Gram &  Bente Steffansen

Authors
  1. Takeshi Tani
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  8. Ikumi Tamai
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Correspondence to Ikumi Tamai.

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Tani, T., Gram, L.K., Arakawa, H. et al. Involvement of Organic Anion Transporting Polypeptide 1a5 (Oatp1a5) in the Intestinal Absorption of Endothelin Receptor Antagonist in Rats. Pharm Res 25, 1085–1091 (2008). https://doi.org/10.1007/s11095-007-9472-4

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  • DOI: https://doi.org/10.1007/s11095-007-9472-4

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