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Cited by 104Histone Deacetylase Inhibitors ResearchRadiopharmaceutical Chemistry and ApplicationsChemical Reactions and Isotopes

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

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Kim, Sung Won, Hooker, Jacob M., Otto, Nicola, Win, Khaing, Muench, Lisa, Shea, Colleen, Carter, Pauline, King, Payton +3 more·2013·Nuclear Medicine and Biology
DOI 10.1016/j.nucmedbio.2013.06.007PMC PMC3769509
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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 90 min. The carbon-11 labeled carboxylic acids were prepared by using (11)CO2 and the appropriate Grignard reagents. [(11)C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min 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. [(11)C]BA showed relatively high uptake in spleen and pancreas whereas [(11)C]PBA showed high uptake in liver and heart. Notably, [(11)C]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.

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  • In primates, only 20% of radio-labeled butyrate remained after 5 minutes post-administration, with the brain taking up less than 0.006%.

    “Notably, a study tracing radio-labeled butyrate in primates found that only 20% remained after 5 minutes post-administration, with the brain only taking up less than 0.006% (Kim et al., 2013).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Kim et al., 2013

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Cited by

Sorted by citations

Authors
Kim, S. W., Hooker, J. M., Otto, N., Win, K., Muench, L., Shea, C., Carter, P., King, P., Reid, A. E., Volkow, N. D., & Fowler, J. S.
Affiliations
  • National Institute on Alcohol Abuse and Alcoholism (US)
  • Harvard University (US)
  • Johannes Gutenberg University Mainz (DE)
  • St. Joseph's University New York (US)
  • Brookhaven National Laboratory (US)
  • Medgar Evers College (US)
  • National Institute on Drug Abuse (US)
Corresponding author
  • Kim, Sung Won
  • Hooker, Jacob M.
ORCID
Venue
Nuclear Medicine and Biology
Publisher
Elsevier BV
Published
2013-10
Volume
40
Issue
7
Pages
912-918
ISSN
0969-8051 (ISSN-L)
DOI
10.1016/j.nucmedbio.2013.06.007
PMC
PMC3769509
OpenAlex
W2045069700
Cited by
104
References
0
Citations by year
2026: 8 · 2025: 5 · 2024: 6 · 2023: 11 · 2022: 16 · 2021: 15 · 2020: 5 · 2019: 13 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 3
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nuclear Medicine and Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • U. S. Department of Energy, Office of Biological and Environmental Research (DE-AC02-98CH10886)
  • NIH Intramural Program of the National Institute on Alcohol Abuse and Alcoholism (1R01DA030321)
  • BNL Science Undergraduate Laboratory Internship Program
  • Deutscher Akademischer Austauschdienst (DAAD)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Chemical Reactions and Isotopes
Keywords
histone deacetylase inhibitors, butyrate, valproic acid, 4-phenylbutyric acid, tissue distribution, baboons, brain uptake, renal excretion, cardiac uptake, epigenetic drugs, teratogenicity
MeSH terms
Animals, Blood Proteins, Brain, Carbon Radioisotopes, Female, Isotope Labeling, Papio, Phenylbutyrates, Radiochemistry, Tissue Distribution, Valproic Acid, Butyric Acid, Positron-Emission Tomography, Histone Deacetylase Inhibitors

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