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Effect of Cyclosporin Analogues and FK506 on Transcellular Transport of Daunorubicin and Vinblastine via P-glycoprotein

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Abstract

Purpose. P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated.

Methods. The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506.

Results. Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity.

Conclusions. In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.

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Author notes

  1. Midori Hirai

    Present address: Department of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, 658, Japan

  2. Yusuke Tanigawara

    Present address: Department of Pharmacy, Kobe University Hospital, Kobe, 650, Japan

  3. Masato Yasuhara

    Present address: Department of Hospital Pharmacy, School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113, Japan

  4. Ryohei Hori

    Present address: Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, 577, Japan

Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, 606-01, Japan

    Kumiko Tanaka, Midori Hirai, Yusuke Tanigawara, Masato Yasuhara, Ryohei Hori & Ken-ichi Inui

  2. Laboratory of Biochemistry, Department of Agricultural Chemistry, Faculty of Agriculture, Kyoto University, Kyoto, 606-01, Japan

    Kazumitsu Ueda

Authors
  1. Kumiko Tanaka
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  2. Midori Hirai
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  4. Masato Yasuhara
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  5. Ryohei Hori
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  6. Kazumitsu Ueda
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  7. Ken-ichi Inui
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Tanaka, K., Hirai, M., Tanigawara, Y. et al. Effect of Cyclosporin Analogues and FK506 on Transcellular Transport of Daunorubicin and Vinblastine via P-glycoprotein. Pharm Res 13, 1073–1077 (1996). https://doi.org/10.1023/A:1016019010339

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