Transport Characteristics of Ebastine and Its Metabolites across Human Intestinal Epithelial Caco-2 Cell Monolayers
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概要
- 論文の詳細を見る
The tansport characteristics of a selective peripheral H_1 receptor antagonist, ebastine, a substrate for cytochrome P450 3A4, and its three major metabolites, i.e., the hydroxy metabolite of ebastine(M-OH), the pharmacologically active metabolite carebastine(Car), and the desbutyrophenone metabolite(des-BP), were studied in cultured human intestinal Caco-2 cells expressing a drug efflux pump, P-glycoprotein(P-gp), on the apical membrane. The polarized transport of[^3H]cyclosporin A(CyA), mediated by P-gp in the basolateral to apical direction across the Caco-2 cell monolayers, was affected by the presence of ebastine in a concentration-dependent manner and significant inhibition was observed at high concentrations(>50μ_M). M-OH(300μ_M)also significantly inhibited whereas Car and des-BP did not. Although no marked polarized transport of[^<14>C]ebastine in a secretory direction was observed in the Caco-2 systems, the flux in the basolateral to apical direction was slightly higher than that in the opposite direction at concentrations less than 30μ_M. [^<14>C]Ebastine(2μ_M)uptake from the apical side was significantly increased in the presence of an excess of cold CyA, suggesting that the efflux process mediated by P-gp may be involved in the ebastine uptake by Caco-2 cells. Collectively, these results indicate that ebastine(and presumably M-OH)is transported via P-gp in Caco-2 cells, however, the affinity for P-gp is very low. It is unlikely that the secretory transport of ebastine mediated by P-gp will dramatically affect overall intestinal absorption in vivo because efficient passive diffusion of this drug should occur due to its high lipophilicity. However, it may be advantageous for its efficient first-pass metabolism.
- 公益社団法人日本薬学会の論文
- 2001-08-01
著者
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Yamashita Fumiyoshi
第一三共 葛西研究開発センター
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Yamashita Fumiyoshi
Department Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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Yamashita Fumiyoshi
Departments Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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Yamashita Fumiyoshi
Graduate School Of Pharmaceutical Sciences Kyoto University
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Hashida Mitsuru
第一三共 葛西研究開発センター
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Hashida Mitsuru
Department Of Basic Pharmaceutics Faculty Of Pharmaceutical Sciences Kyoto University
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Hashida Mitsuru
京都大学 薬学研究科病態情報薬学
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Hashida Mitsuru
Dep. Of Drug Delivery Res. Graduate School Of Pharmaceutical Sciences Kyoto Univ. 46-29 Yoshidashimo
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Hashida Mitsuru
Inst. Of Integrated Cell-material Sciences (icems) Kyoto Univ.
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Yamashita Fumiyoshi
Dep. Of Drug Delivery Res. Graduate School Of Pharmaceutical Sciences Kyoto Univ. 46-29 Yoshidashimo
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Shimizu K
Department Of Pharmaceutics Hoshi University
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Hashida M
Department Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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Hashida Mitsuru
Graduate School Of Pharmaceutical Sciences Kyoto University
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YAMASHITA Fumiyoshi
京大院薬
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HASHIDA Mitsuru
京大院薬
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TAKAKURA Yoshinobu
Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University
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IMAMURA Yuichiro
Departments of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
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SHIMIZU Kazuteru
Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University
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YAMAOKA Kiyoshi
Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University
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Takakura Yoshinobu
Department Of Basic Pharmaceutics Faculty Of Pharmaceutical Sciences Kyoto University
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Takakura Yoshinobu
Department Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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Yamaoka Kiyoshi
Biopharmaceutics And Drug Metabolism Graduate School Of Pharmaceutical Sciences Kyoto University
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Yamashita Fumiyoshi
Dep. Of Drug Delivery Res. Graduate School Of Pharmaceutical Sciences Kyoto Univ.
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Imamura Yuichiro
Departments Of Drug Delivery Research Graduate School Of Pharmaceutical Sciences Kyoto University
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