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Biological and Pharmaceutical Bulletin
Vol. 32 (2009) No. 1 P 74-78



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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 (Papp BL to AP/Papp 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 (Papp 17.1±0.32×10−6 cm/s) while the efflux was inhibited (Papp 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 (Papp 20.3±0.1×10−6 cm/s), whereas this effect was completely abrogated by indomethacin (Papp 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.

Copyright © 2009 The Pharmaceutical Society of Japan

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