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

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.