title: Toxicological and metabolic considerations for histone deacetylase inhibitors.
abstract: BACKGROUND
  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 in vitro setting. Proving their efficacy in vivo was much more difficult, since the effects of an administrated drug strongly depend on its absorption, distribution, metabolism and excretion.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: VUB, Toxicology, Laarbeeklaan 103, Brussels 1090, Belgium. jfraczek@vub.ac.be
authors.forename: Joanna
authors.initials: J
authors.lastname: Fraczek
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
mesh_terms: D001549:Benzamides / Q000493:pharmacokinetics / Q000633:toxicity; D002986:Clinical Trials as Topic; D047630:Depsipeptides / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000633:toxicity; D011725:Pyridines / Q000493:pharmacokinetics / Q000633:toxicity; D000077337:Vorinostat; D014882:Water-Electrolyte Balance
chemical_list: D001549:Benzamides; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; D000077337:Vorinostat; C087123:romidepsin