TY - JOUR
T1 - Enantiomer-specific pharmacokinetics of D,L-3-hydroxybutyrate: Implications for the treatment of multiple acyl-CoA dehydrogenase deficiency
AU - van Rijt, Willemijn J.
AU - van Hove, Johan L. K.
AU - Vaz, Frédéric M.
AU - Havinga, Rick
AU - Allersma, Derk P.
AU - Zijp, Tanja R.
AU - Bedoyan, Jirair K.
AU - Heiner-Fokkema, M. R.
AU - Reijngoud, Dirk-Jan
AU - Geraghty, Michael T.
AU - Wanders, Ronald J. A.
AU - Oosterveer, Maaike H.
AU - Derks, Terry G. J.
N1 - Funding Information: Aycha Bleeker, Arno G. van Cruchten, Dr Marisa Friederich, Kaz Knight, Prof Dr Folkert Kuipers, Prof Dr Francjan J. van Spronsen, and Danique van Vliet are gratefully acknowledged for their valuable contributions to the sample preparation and analysis, and valuable discussions. The authors are grateful to Donna Herber of Trumacro for the provision of D,L-3-HB to patient 2. This work was supported by grants from ?Stofwisselkracht? (2017-09) and the ?Vereniging tot bevordering van onderzoek naar Erfelijke Stofwisselingsziekten in het Nederlandse taalgebied? (ESNLT) (2017). Pharmaceutical companies did not contribute in this study. The MD/PhD scholarship of Willemijn J. van Rijt is funded by the Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen (MD/PhD 15-30). Maaike H. Oosterveer holds a Rosalind Franklin Fellowship from the University of Groningen. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Publisher Copyright: © 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - 3-hydroxybutyrate
KW - enantiomer
KW - inborn error of metabolism
KW - ketone bodies
KW - multiple acyl-CoA dehydrogenase deficiency
KW - pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85101476525&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12365
DO - https://doi.org/10.1002/jimd.12365
M3 - Article
C2 - 33543789
SN - 0141-8955
VL - 44
SP - 926
EP - 938
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 4
ER -