Enantiomer-specific pharmacokinetics of D,L-3-hydroxybutyrate: Implications for the treatment of multiple acyl-CoA dehydrogenase deficiency

J Inherit Metab Dis. 2021 Jul;44(4):926-938. doi: 10.1002/jimd.12365. Epub 2021 Feb 15.


D,L-3-hydroxybutyrate (D,L-3-HB, a ketone body) treatment has been described in several inborn errors of metabolism, including multiple acyl-CoA dehydrogenase deficiency (MADD; glutaric aciduria type II). We aimed to improve the understanding of enantiomer-specific pharmacokinetics of D,L-3-HB. Using UPLC-MS/MS, we analyzed D-3-HB and L-3-HB concentrations in blood samples from three MADD patients, and blood and tissue samples from healthy rats, upon D,L-3-HB salt administration (patients: 736-1123 mg/kg/day; rats: 1579-6317 mg/kg/day of salt-free D,L-3-HB). D,L-3-HB administration caused substantially higher L-3-HB concentrations than D-3-HB. In MADD patients, both enantiomers peaked at 30 to 60 minutes, and approached baseline after 3 hours. In rats, D,L-3-HB administration significantly increased Cmax and AUC of D-3-HB in a dose-dependent manner (controls vs ascending dose groups for Cmax : 0.10 vs 0.30-0.35-0.50 mmol/L, and AUC: 14 vs 58-71-106 minutes*mmol/L), whereas for L-3-HB the increases were significant compared to controls, but not dose proportional (Cmax : 0.01 vs 1.88-1.92-1.98 mmol/L, and AUC: 1 vs 380-454-479 minutes*mmol/L). L-3-HB concentrations increased extensively in brain, heart, liver, and muscle, whereas the most profound rise in D-3-HB was observed in heart and liver. Our study provides important knowledge on the absorption and distribution upon oral D,L-3-HB. The enantiomer-specific pharmacokinetics implies differential metabolic fates of D-3-HB and L-3-HB.

Keywords: 3-hydroxybutyrate; enantiomer; inborn error of metabolism; ketone bodies; multiple acyl-CoA dehydrogenase deficiency; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / administration & dosage*
  • 3-Hydroxybutyric Acid / pharmacokinetics*
  • Acyl-CoA Dehydrogenase / genetics
  • Administration, Oral
  • Animals
  • Chromatography, Liquid
  • Humans
  • Male
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / drug therapy*
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / genetics
  • Rats
  • Rats, Wistar
  • Tandem Mass Spectrometry


  • Acyl-CoA Dehydrogenase
  • 3-Hydroxybutyric Acid