In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors.
Histone deacetylase inhibitors (HDACIs) are emerging as a new class of therapeutic agents with potent antitumor activities in a broad spectrum of human cancers. In this study, the in vitro plasma stability, permeability, solubility, and lipophilicity (log D) of two mercaptoacetamide-based HDACIs (coded as W2 and S2) were evaluated and compared to Vorinostat (SAHA). The results demonstrated that the compounds manifested high solubility in HCl (pH 1.2) but lower in PBS (pH 7.4) than SAHA. Moreover, mercaptoacetamide-based HDACIs exhibited higher lipophilicity values compared to SAHA. The permeability of these compounds was evaluated using the Caco-2 cell monolayer as a model of the intestinal mucosa. The Caco-2 studies revealed that the compounds S2 and W2 are highly permeable with apparent permeability coefficients (P(app)) in the apical to basolateral direction of 7.33 x 10(-6) and 15.0 x 10(-6)cm/s, respectively. The in vitro stability was determined in human, mouse, porcine and rat plasma. Data showed that the compound W2 is more stable in human and rat plasma and the S2 is more stable in all plasma species than SAHA. Taken together, these results indicate that the mercaptoacetamide-based HDACIs possess favorable solubility, lipophilicity, permeability and plasma stability features.
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Roula
R
Konsoula
Mira
M
Jung
D000081:Acetamides / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D010539:Permeability; D051381:Rats; D012995:Solubility; D013552:Swine; D000077337:Vorinostat
D000081:Acetamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat