title: Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET.
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.
authors.affiliation: Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Upton, NY, USA. Electronic address: sunny.kim@nih.gov.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.forename: Nicola
authors.initials: N
authors.lastname: Otto
authors.forename: Khaing
authors.initials: K
authors.lastname: Win
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Reid
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D020148:Butyric Acid / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D010215:Papio; D010654:Phenylbutyrates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D014018:Tissue Distribution; D014635:Valproic Acid / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D002250:Carbon Radioisotopes; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D020148:Butyric Acid; D014635:Valproic Acid; C075773:4-phenylbutyric acid
keywords: (11)C]valproic acid; Histone deacetylase (HDAC); Pharmacokinetics; Positron emission tomography; [(11)C]4-phenylbutyric acid; [(11)C]butyric acid
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