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Cited by 108Histone Deacetylase Inhibitors ResearchDrug Solubulity and Delivery SystemsAnalytical Methods in Pharmaceuticals

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors

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Konsoula, Roula, Jung, Mira·2008·International Journal of Pharmaceutics
DOI 10.1016/j.ijpharm.2008.05.001PMC PMC2565275
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Abstract

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.

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  • The novel HDAC inhibitors W2 (mercaptoacetamide-based class II) and I2 (hydroxamide-based class I and II) have improved pharmacological properties, including longer half-life and greater blood-brain barrier penetration, compared to commercially available HDACIs.

    “We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2)”

    From Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease (2013) · cites this paper as Konsoula and Jung, 2008

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Authors
Konsoula, R., & Jung, M.
Affiliations
Georgetown University Medical Center (US)
Corresponding author
Jung, Mira
ORCID
Jung, Mira
Venue
International Journal of Pharmaceutics
Publisher
Elsevier BV
Published
2008-09
Volume
361
Issue
1-2
Pages
19-25
ISSN
0378-5173 (ISSN-L)
DOI
10.1016/j.ijpharm.2008.05.001
PMC
PMC2565275
OpenAlex
W2060928309
Cited by
108
References
39
Citations by year
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FWCI
0.96
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • International Journal of Pharmaceutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (P02 CA74175, P01CA074175)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Keywords
histone deacetylase inhibitors, vorinostat, plasma stability, intestinal permeability, solubility, lipophilicity, Caco-2 cell monolayers, anticancer agents, drug absorption
MeSH terms
Vorinostat, Acetamides, Animals, Antineoplastic Agents, Chemistry, Pharmaceutical, Drug Stability, Enzyme Inhibitors, Humans, Hydrogen-Ion Concentration, Hydroxamic Acids, Intestinal Mucosa, Neoplasms, Permeability, Solubility, Swine, Caco-2 Cells, Mice, Rats, Histone Deacetylase Inhibitors, Hydrophobic and Hydrophilic Interactions

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