In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol

Food Chem Toxicol. 2021 Jan:147:111859. doi: 10.1016/j.fct.2020.111859. Epub 2020 Nov 17.


A novel ketone ester, bis hexanoyl (R)-1,3-butanediol (BH-BD), has been developed as a means to elevate blood ketones, for use as an energy substrate and a signaling metabolite. The metabolism of BH-BD and its effects on blood beta-hydroxybutyrate (BHB) levels was evaluated in various in vitro matrices and through analysis of plasma collected from Sprague Dawley rats and C57/BL6 mice in two oral gavage studies. A well-characterized ketone ester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (HB-BHB), was used as an active control throughout. In vitro assay results demonstrated that BH-BD likely remains intact in the stomach and is hydrolyzed in the small intestine into hexanoate and (R)-1,3-butanediol. If absorbed intact, BH-BD is subject to hydrolysis by non-CYP enzymes in liver and esterases in plasma. If BH-BD reaches the lower intestine it is metabolized by gut flora. Plasma BHB delivery increased in a dose-dependent manner in rats and mice following oral administration of BH-BD. All doses of BH-BD were well tolerated. At doses over 3 g/kg, BHB delivery was similar between BH-BD and HB-BHB. The results of these studies support the hydrolysis of BH-BD into hexanoate and (R)-1,3-butanediol which are metabolized into BHB, delivering a well-tolerated, sustained and dose-dependent increase in plasma BHB in rodents.

Keywords: Ketone ester; Ketones; Pharmacokinetics; d-β-hydroxybutyrate.

MeSH terms

  • Administration, Oral
  • Animals
  • Butylene Glycols / chemistry*
  • Butylene Glycols / pharmacokinetics*
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Gastrointestinal Contents / chemistry
  • Humans
  • Male
  • Mice
  • Microsomes, Liver / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Statistics as Topic


  • Butylene Glycols