Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET

Sung Won Kim, Jacob M. Hooker, Nicola Otto, Khaing Win, Lisa Muench, Colleen Shea, Pauline Carter, Payton King, Alicia E. Reid, Nora D. Volkow, Joanna S. Fowler

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90min. The carbon-11 labeled carboxylic acids were prepared by using 11CO2 and the appropriate Grignard reagents. [11C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30min after their administration respectively. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [11C]BA showed relatively high uptake in spleen and pancreas whereas [11C]PBA showed high uptake in liver and heart. Notably, [11C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.

Original languageEnglish
Pages (from-to)912-918
Number of pages7
JournalNuclear Medicine and Biology
Volume40
Issue number7
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • C]valproic acid
  • Histone deacetylase (HDAC)
  • Pharmacokinetics
  • Positron emission tomography
  • [C]4-phenylbutyric acid
  • [C]butyric acid

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