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 profile. 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 11CO2 and the appropriate Grignard reagents. [11C]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 was 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. [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.

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…In addition, VPA was used as the total HDACs inhibitor to detect the cardioprotection in the OVE26 type 1 diabetes mice too. Although butyrate was used in the previous studies as total HDAC inhibitor (15), pharmacokinetic studies have confirmed its lower cardiac distribution, compared to VPA (41, 42). In addition, phase II/III clinical trials have confirmed that VPA is a safe medicine for the therapy some cancers (43, 44).…”

The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats

“…Interestingly, while NaB significantly increases IGF-1 in peripheral tissues in the post stroke animal, there was no elevation of IGF-1 in the brain with this treatment. In a study examining the biodistribution of exogenous fatty acids including n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid in primates [59], only a very small amount (<0.006%) is taken up by the brain, whereas majority of these fatty acids were taken up by spleen (BA) and liver (PBA). Considering this biodistribution, it is not surprising that NaB was most effective in IGF-1 level in liver, spleen, and serum.…”

The Role of Butyrate, A Histone Deacetylase Inhibitor in Diabetes Mellitus: Experimental Evidence for Therapeutic Intervention

“…Additionally, butyrate has several other pharmacological properties such as anti-infllamatory, antioxidative, immunomodulatory and chemoprotective, which can add further value to subjects with diabetes. However, butyrate has short half-life of 10-15 min due to its rapid uptake and metabolism by normal cells, which dampens its therapeutic utilization [88]. This problem can be overcome with more stable butyrate derivatives like N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA or phenylalanine-butyramide), which can provide a consistent effective concentration in systemic circulation [89].…”