ArticleBiological & pharmaceutical bulletin2009
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.
Article in Biological & pharmaceutical bulletin, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 13 citations in OpenAlex.
- Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95.Molecular pharmaceutics · 2015Article
- HDAC inhibitor-induced drug resistance involving ATP-binding cassette transporters (Review).Oncology letters · 2015Article
- Preclinical studies of YK-4-272, an inhibitor of class II histone deacetylases by disruption of nucleocytoplasmic shuttling.Pharmaceutical research · 2012Article
- Assessment and modulation of phillyrin absorption by P-gp using Caco-2 cells and MDR1-MDCKII cells.European journal of drug metabolism and pharmacokinetics · 2011Article
- Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors.Molecular cancer therapeutics · 2009Article
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
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.
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