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
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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DOI：
10.1248/bpb.32.74
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发表时间：
2009-01-01
影响因子：
2
通讯作者：
Jung, Mira
中科院分区：
文献类型：
--
作者：
Konsoula, Zacharoula;Jung, Mira
口服生物利用度是开发候选药物的重要标准之一。本研究利用Caco-2细胞研究了巯基乙酰胺基组蛋白脱乙酰酶（HDAC）抑制剂（编码W2）的吸收特性和外排机制。基底外侧到根尖（BL - AP）通量是根尖到基底外侧（AP - BL）通量的1.85倍，表明W2的转运是不对称的。这种不对称性与多药耐药相关蛋白1 （MRP1）和p -糖蛋白（P-gp）有关，这些蛋白的特异性抑制证明了这一点。在P-gp有效抑制剂异拉帕米和环孢素A的作用下，W2的表观通透率（P-app BL / AP/P-app AP/ BL）分别从1.85降低到0.73和1.03，从根尖到基底外侧的吸收分别从13.3 +/- 0.2x 10(-6) cm/s提高到17.3 +/- 0.12 x 10(-6) cm/s和19 +/- 0.3 x 10(-6) cm/s。加入奎尼丁（P-gp和MRPI混合抑制剂）后，W2从根尖侧的渗透明显增加（P-app 17.1 +/- 0.32 × 10(-6) cm/s），而外排受到抑制（P-app 21.3 +/- 0.19 × 10(-6) cm/s）。此外，还评估了MRPI抑制剂、吲哚美辛和n -苄基吲哚美辛（NBI）的影响。NBI治疗降低了W2基底外侧到根尖的通量（P-app 20.3 +/- 0.1 x 10(-6) cm/s），而吲哚美辛（P-app 11 +/- 0.4 x 10(-6) cm/s）完全消除了这种影响。结果表明，P-gp和MRPI转运体能够介导W2的外排，并可能在其口服吸收中发挥重要作用。
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 +/- 0.2x 10(-6) cm/s to 17.3 +/- 0.12 x 10(-6) CM/S and 19 +/- 0.3 x 10(-6) cm/s, respectively. Upon addition of quinidine, a mixed P-gp and MRPI inhibitor, the permeation of W2 from the apical side was significantly increased (P-app 17.1 +/- 0.32x 10(-6) cm/s) while the efflux was inhibited (P-app 21.3 +/- 0.19 x 10(-6) cm/s). Furthermore, the influence of the MRPI 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 x 10(-6) cm/s), whereas this effect was completely abrogated by indomethacin (P-app 11 +/- 0.4 X 10(-6) cm/s). The results suggest that P-gp and MRPI transporters are capable of mediating the efflux of W2 and might play a significant role in its oral absorption.