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Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells

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Abstract

Purpose

To investigate the underlying mechanism of low bioavailabilities of the water-soluble camptothecin derivatives, belotecan and topotecan.

Methods

The bioavailability of belotecan and topotecan in rats was determined following oral administration of each drug at a dose of 5 mg/kg body weight. The vectorial transport of each drug was measured in Caco-2 and engineered MDCK II cells.

Results

The bioavailability of belotecan (11.4%) and topotecan (32.0%) in rats was increased to 61.5% and 40.8%, respectively, by the preadministration of CsA at a dose of 40 mg/kg. Contrary to the absorptive transport, the secretory transport of these drugs across the Caco-2 cell monolayer was concentration-dependent, saturable, and significantly inhibited by the cis presence of verapamil (a P-gp substrate), MK-571 (an MRP inhibitor), bromosulfophthalein (BSP, an MRP2 inhibitor), fumitremorgin C (FTC, a BCRP inhibitor) and cyclosporine A (CsA, an inhibitor of P-gp and BCRP, and a substrate of P-gp) suggesting the involvement of these transporters, which could be further confirmed in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells.

Conclusion

The involvement of secretory transporters P-gp, MRP2 and BCRP, particularly for belotecan, as well as a low passive permeability, appears to be responsible for the low bioavailability of belotecan and topotecan.

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Abbreviations

ABC:

ATP-binding cassette

BCRP:

breast cancer resistance protein

BSP:

bromosulfophtahlein

CPT:

20-(s)-camptothecin

CsA:

cyclosporine A

DMEM:

Dulbecco’s modified Eagle’s medium

FTC:

fumitremorgin

HBSS:

Hank’s balanced salt solution

HEPES:

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

MDCK:

Mardine–Darby canine kidney

MK-571:

3-([{3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl}-{(3-dimethylamino-3-oxopropyl)-thio}-methyl]-thio) propanoic acid

MRP2:

multidrug resistance protein 2

P-gp:

P-glycoprotein

SD:

Sprague–Dawley

TEER:

transepithelial electrical resistance

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Acknowledgments

We sincerely thank Dr. Borst at The Netherlands Cancer Institute (Amsterdam, The Netherlands) for providing MDCKII/wt, MDCKII/P-gp, MDCKII/MRP2, and MDCKII/BCRP cells. This work was supported by the Korea Science and Engineering Foundation (KOSEF) through the National Research Lab. Program funded by the Ministry of Science and Technology (No.R0A2006000102900).

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Authors and Affiliations

  1. National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-742, Republic of Korea

    Hong Li, Hyo-Eon Jin, Wooyoung Kim, Dae-Duk Kim, Suk-Jae Chung & Chang-Koo Shim

  2. Department of Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb R&D, Princeton, New Jersey, USA

    Yong-Hae Han

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  1. Hong Li
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Correspondence to Chang-Koo Shim.

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Hong Li and Hyo-Eon Jin have contributed equally to this work.

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Li, H., Jin, HE., Kim, W. et al. Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells. Pharm Res 25, 2601–2612 (2008). https://doi.org/10.1007/s11095-008-9678-0

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  • DOI: https://doi.org/10.1007/s11095-008-9678-0

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