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Inhibitory Potencies of 1,4-dihydropyridine Calcium Antagonists to P-glycoprotein-Mediated Transport: Comparison with the Effects on CYP3A4

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Abstract

Purpose. Recently, we clarified the inhibitory effects of 13 kinds of 1,4-dihydropyridine calcium antagonists on human cytochrome P450 (CYP) 3A4. It has been reported that the substrates and/or inhibitors are overlapped between CYP3A4 and P-glycoprotein (P-gp). The purpose of this study was to investigate the inhibitory effects of 13 kinds of 1,4-dihydropyridine calcium antagonists on P-gp-mediated transport in order to evaluate the overlapping specificity of the inhibitors between P-gp and CYP3A4.

Methods. The transcellular transports of [3H]daunorubicin or [3H]digoxin by monolayers of LLC-GA5-COL150 cells in which P-gp was overexpressed were measured in the presence or absence of the 1,4-dihydropyridine calcium antagonists.

Results. The transport of [3H]daunorubicin was strongly inhibited by manidipine, barnidipine, benidipine, (−)-efonidipine, nicardipine, (+)-efonidipine, and amlodipine with the IC50 values of 4.6, 8.6, 9.5, 17.3, 17.5, 20.6, and 22.0 μM, respectively. The transport of [3H]digoxin was strongly inhibited by benidipine, nicardipine, barnidipine, and manidipine.

Conclusions. It was clarified that 13 kinds of 1,4-dihydropyridine calcium antagonists have different inhibitory potencies and substrate specificities to the transport of [3H]daunorubicin or [3H]digoxin. Some compounds did not demonstrate the overlapping specificity for inhibition between P-gp and CYP3A4. It was also clarified that ni- cardipine, benidipine, manidipine, and barnidipine were strong inhibitors of P-gp as well as CYP3A4.

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Authors and Affiliations

  1. Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, Kanazawa, 920-0934, Japan

    Miki Katoh & Miki Nakajima

  2. Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, Kanazawa, 920-0934, Japan

    Tsuyoshi Yokoi

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  1. Miki Katoh
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  2. Miki Nakajima
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  3. Hiroshi Yamazaki
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  4. Tsuyoshi Yokoi
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Katoh, M., Nakajima, M., Yamazaki, H. et al. Inhibitory Potencies of 1,4-dihydropyridine Calcium Antagonists to P-glycoprotein-Mediated Transport: Comparison with the Effects on CYP3A4. Pharm Res 17, 1189–1197 (2000). https://doi.org/10.1023/A:1007568811691

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