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标题：Involvement of P-glycoprotein and Multidrug Resistance Associated Protein 1 on the Transepithelial Transport of a Mercaptoacetamide-Based Histone-Deacetylase Inhibitor in Caco-2 Cells
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作者：Zacharoula Konsoula ; Mira Jung
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2009
卷号：32
期号：1
页码：74-78
DOI：10.1248/bpb.32.74
出版社：The Pharmaceutical Society of Japan
摘要：Oral bioavailability is one of the important criteria for development of a drug-lead candidate. In this study, the absorptive characteristics and the efflux mechanism of a mercaptoacetamide-based histone deacetyalse (HDAC) inhibitor, coded as W2, were investigated using Caco-2 cells. The transport of W2 was asymmetric as indicated by 1.85 fold higher basolateral to apical (BL to AP) than apical to basolateral (AP to BL) flux. Such asymmetry was associated with multidrug resistance associated protein 1 (MRP1) and P-glycoprotein (P-gp), as evidenced by specific inhibition of these proteins. In the presence of verapamil and cyclosporin A, potent inhibitors of P-gp, the apparent permeability ratio ( P _app BL to AP/ P _app AP to BL) of W2 was decreased from 1.85 to 0.73 and 1.03, respectively, and the absorption from apical to basolateral side was enhanced from 13.3±0.2×10⁻⁶ cm/s to 17.3±0.12×10⁻⁶ cm/s and 19±0.3×10⁻⁶ cm/s, respectively. Upon addition of quinidine, a mixed P-gp and MRP1 inhibitor, the permeation of W2 from the apical side was significantly increased ( P _app 17.1±0.32×10⁻⁶ cm/s) while the efflux was inhibited ( P _app 21.3±0.19×10⁻⁶ cm/s). Furthermore, the influence of the MRP1 inhibitors, indomethacin and N -benzyl-indomethacin (NBI) was evaluated. NBI treatment attenuated the basolateral to apical flux of W2 ( P _app 20.3±0.1×10⁻⁶ cm/s), whereas this effect was completely abrogated by indomethacin ( P _app 11±0.4×10⁻⁶ cm/s). The results suggest that P-gp and MRP1 transporters are capable of mediating the efflux of W2 and might play a significant role in its oral absorption.
关键词：histone deacetylase inhibitor;mercaptoacetamide;P-glycoprotein;multidrug resistance associated protein 1;caco-2 cell line