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+/-0.2x10(-6) cm/s to 17.3+/-0.12x10(-6) cm/s and 19+/-0.3x10(-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+/-0.32x10(-6) cm/s) while the efflux was inhibited (P(app) 21.3+/-0.19x10(-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+/-0.1x10(-6) cm/s), whereas this effect was completely abrogated by indomethacin (P(app) 11+/-0.4x10(-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.
Konsoula
Zacharoula
Z
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1482, USA.
Jung
Mira
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000230:Adenocarcinoma; D000704:Analysis of Variance; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D056572:Histone Deacetylase Inhibitors; D014700:Verapamil; C088840:deaD protein, E coli; D053487:DEAD-box RNA Helicases