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Model Analysis of the Concentration-Dependent Permeability of P-gp Substrates

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Abstract

Purpose

Recently, it was reported that the apparent Michaelis-Menten constant (Km(app)) of a P-glycoprotein (P-gp) substrate, defined for the extracellular substrate concentration, increases as the P-gp expression level in the cell increases. By its nature, the Km value should not depend on the level of P-gp expression. The purpose of this study is to establish a model which can estimate the Km value independent of the P-gp expression level in cells.

Methods

The previously reported concentration-dependent permeability of verapamil, quinidine, and vinblastine in MDR1-MDCKII, P-gp-highly induced Caco-2, P-gp-induced Caco-2, normal Caco-2, and MDR1-knockdown Caco-2 cells data were analyzed using a model in which the Km value was defined for the intracellular substrate concentration.

Results

The estimated Km values defined for the substrate concentration inside the cells were almost the same among various cells with different levels of P-gp expression. The estimated Vmax values were approximately proportional to the P-gp expression level.

Conclusion

The established kinetic model was found to be rational based on the results that the Km values of P-gp substrates were about the same for cells expressing various levels of P-gp, while the Vmax values were proportional to the expression levels of P-gp.

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Authors and Affiliations

  1. Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan

    Tatsuhiko Tachibana, Motohiro Kato & Tetsuya Mitsui

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

    Satoshi Kitamura & Yuichi Sugiyama

  3. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Kanazawa, 920-1192, Japan

    Yoshiyuki Shirasaka

  4. Faculty of Pharmaceutical Sciences, Setsunan University, 45–1 Nagaotoge-cho, Hirakata, Osaka, 573–0101, Japan

    Shinji Yamashita

Authors
  1. Tatsuhiko Tachibana
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  2. Satoshi Kitamura
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  3. Motohiro Kato
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  4. Tetsuya Mitsui
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  5. Yoshiyuki Shirasaka
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  6. Shinji Yamashita
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  7. Yuichi Sugiyama
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Correspondence to Tatsuhiko Tachibana.

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Tachibana, T., Kitamura, S., Kato, M. et al. Model Analysis of the Concentration-Dependent Permeability of P-gp Substrates. Pharm Res 27, 442–446 (2010). https://doi.org/10.1007/s11095-009-0026-9

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  • DOI: https://doi.org/10.1007/s11095-009-0026-9

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