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

• Published in: Nuclear medicine and biology Vol. 40; no. 7; pp. 912 - 918
• Main Authors: Kim, Sung Won, Hooker, Jacob M, Otto, Nicola, Win, Khaing, Muench, Lisa, Shea, Colleen, Carter, Pauline, King, Payton, Reid, Alicia E, Volkow, Nora D, Fowler, Joanna S
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2013
• Subjects: 11C (Carbon 11); 11C]valproic acid; [11C]4-phenylbutyric acid; [11C]BA (butyric acid); [11C]butyric acid; [11C]PBA (4-phenylbutyric acid); [11C]VPA (valproic acid); Animals; Blood Proteins - metabolism; Brain - diagnostic imaging; Brain - metabolism; Butyric Acid - blood; Butyric Acid - metabolism; Butyric Acid - pharmacokinetics; Carbon Radioisotopes; Female; HDAC (histone deacetylase); Histone deacetylase (HDAC); Histone Deacetylase Inhibitors - blood; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylase Inhibitors - pharmacokinetics; Isotope Labeling; Papio; PET (positron emission tomography); phamacokinetics; Pharmacokinetics; Phenylbutyrates - blood; Phenylbutyrates - metabolism; Phenylbutyrates - pharmacokinetics; Positron emission tomography; RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; Radiochemistry; Radiology; Tissue Distribution; Valproic Acid - blood; Valproic Acid - metabolism; Valproic Acid - pharmacokinetics; Histone deacetylase (HDAC); [ 11C]butyric acid; Pharmacokinetics; [ 11C]4-phenylbutyric acid; Positron emission tomography; 11C]valproic acid; [11C]4-phenylbutyric acid; [11C]butyric acid; [C]butyric acid; C]valproic acid; [C]4-phenylbutyric acid
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2013.06.007

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 using11 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.