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Multiple drug transporters mediate the placental transport of sulpiride

  • Toxicokinetics and Metabolism
  • Published:
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Abstract

Sulpiride is a typical antipsychotic drug for the treatment of schizophrenia, depression and other psychological disorders. It has been proven that a small amount of sulpiride could cross the human placenta using an ex vivo placental perfusion model. However, the placental transfer mechanism has not been elucidated. Considering the structure of sulpiride, we speculated that the transporters expressed in placenta might be involved in sulpiride uptake across the blood–placenta barrier. The aim of our study was to determine which transporters contributed to the placental transfer of sulpiride. Our results revealed that sulpiride was a substrate of human organic cation transporter (hOCT) 3, human multidrug resistance protein (hMDR) 1 and human breast cancer resistance protein (hBCRP) using transfected cells expressing respective transporters. In addition, the accumulation of sulpiride in BeWo cells (a human choriocarcinoma cell line) was obviously affected by inhibitors of carnitine/organic cation transporter (OCTN) 2, MDR1 and BCRP. The accumulation of sulpiride in primary human trophoblast cells was obviously affected by inhibitors of OCT3, OCTN1 and OCTN2. The above results indicate that hOCTN1 and hOCTN2 likely contribute to the sulpiride uptake from maternal circulation to trophoblast cells, while hMDR1 and hBCRP mediate the efflux from trophoblast cells to maternal circulation, and hOCT3 probably is involved in the bidirectional transport of sulpiride between the placenta and fetal blood.

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Abbreviations

P app :

Apparent permeability

SLC:

Solute carrier

ABC:

ATP-Binding cassette

MDCK:

Madin–Darby canine kidney

HEK293:

Human embryonic kidney 293

LLC-PK1:

Lilly Laboratories Cell-Porcine Kidney 1

OCT:

Organic cation transporter

OAT:

Organic anion transporter

OCTN:

Carnitine/organic cation transporter

BCRP:

Breast cancer resistance protein

MDR1:

Multidrug resistance protein 1

MRP:

Multidrug resistance-associated protein

CNT:

Concentrative nucleoside transporter

PEPT:

Peptide transporter

OATP:

Organic anion-transporting polypeptide

MPP+ :

1-Methyl-4-phenylpyridiniumiodide

D22:

Decynium-22

6-CF:

6-Carboxyl fluorescein

EGT:

l-Ergothioneine

CsA:

Cyclosporine A

MTX:

Methotrexate

DAC:

Decitabine

PHTCs:

Primary human trophoblast cells

SDS:

Sodium dodecyl sulfonate

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Acknowledgements

We want to thank Prof. Kang Sun and Rujuan Zuo for their help in the isolation of primary human trophoblast cells. This work was supported by National Natural Science Foundation of China [Grant Nos. 81373474, 81302833] and Zhejiang Province Natural Science Foundation of China [Grant No. LY17H310003].

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Authors and Affiliations

  1. Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China

    Mengru Bai, Zhiyuan Ma, Yayun Weng, Xi Yang, Ting Jiang & Huidi Jiang

  2. Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Dongli Sun & Caihong Zheng

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  1. Mengru Bai
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  2. Zhiyuan Ma
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  7. Ting Jiang
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  8. Huidi Jiang
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Contributions

Conceived of or designed study: MB, ZM, DS, CZ, YW and HJ. Performed research: MB, ZM, XY, TJ. Analyzed data: MB, ZM and HJ. Wrote the paper: MB, CZ, DS, ZM and HJ.

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Correspondence to Huidi Jiang.

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The authors declare that they have no conflicts of interest.

Ethical standards

The primary human trophoblast cell studies have been approved by the Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University. And all pregnant women signed their informed consent prior to the experiment.

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Bai, M., Ma, Z., Sun, D. et al. Multiple drug transporters mediate the placental transport of sulpiride. Arch Toxicol 91, 3873–3884 (2017). https://doi.org/10.1007/s00204-017-2008-8

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