Toxicological and metabolic considerations for histone deacetylase inhibitors. (April 2013)

• Record Type: Journal Article
• Authors: Fraczek, Joanna; Vanhaecke, Tamara; Rogiers, Vera
• Is Part Of: Expert opinion on drug metabolism and toxicology. Volume 9:Number 4(2013:Apr.)
• Page Start: 441
• Page End: 457
• Publication Date: 2013-04
• Subjects: Drugs -- Toxicology -- Periodicals; Drugs -- Metabolism -- Periodicals; 615.7
• DOI: 10.1517/17425255.2013.754011
• Languages: English
• ISSNs: 1742-5255

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Introduction:</italic> </bold> Vorinostat and romidepsin were the first histone deacetylase (HDAC) inhibitors (HDi) that fulfilled the preclinical promise of anticancer potential in clinical trials. Nevertheless, they merely opened a new chapter in the history of cancer therapy. Demonstration of their antitumor activity was a straightforward task in <italic>in vitro</italic> setting. Proving their efficacy <italic>in vivo</italic> was much more difficult, since the effects of an administrated drug strongly depend on its absorption, distribution, metabolism and excretion.</p> <p> <bold> <italic>Areas covered:</italic> </bold> This article summarizes clinical data on the pharmacokinetic properties of HDi that are currently at more advanced stages of clinical development. Specific attention is paid to the metabolic pathways. Moreover, a comprehensive overview of HDi-related adverse effects is given.</p> <p> <bold> <italic>Expert opinion:</italic> </bold> At this moment, HDi form one of the most interesting classes of therapeutics, yet their efficacy and safety profiles could still be improved by i) designing better formulations, ii) more extensive characterization of their disposition at the preclinical stage, iii) targeting of individual disease-related deacetylase isoforms and/or their complexes, iv) selecting a target patient population with the highest probability of response based on molecular signatures.</p> </abstract>