Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions.
Level 5 - mechanism / opinion, no new human data
In vitro bench research using pooled human and animal liver fractions
PubMed 40087222 · doi:10.1208/s12248-025-01044-7
What was done
Researchers evaluated the in vitro hepatic metabolic kinetics and clearance of the Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate, KE), its metabolite (R)-1,3-butanediol ((R)-1,3-BD), and the intermediate aldol. Kinetic parameters were measured using pooled human (mixed gender) and pooled rat (male and female) liver fractions.
What was found
KE exhibited rapid, non-saturable clearance in both human and rat liver fractions at concentrations up to 15,000 µM. Aldol also showed rapid, non-saturable hepatic clearance in human liver fractions. Conversely, (R)-1,3-BD demonstrated saturable metabolism with Km and Vmax values of 8,000 µM and 27.1 nmol/min/mg protein in humans, 19,300 µM and 113.5 nmol/min/mg protein in male rats, and 11,910 µM and 75.8 nmol/min/mg protein in female rats.
Why it matters
This study provides specific kinetic parameters for exogenous ketone ester metabolism, showing that while the parent ester and aldol intermediate clear non-saturably, hepatic metabolism of (R)-1,3-butanediol is capacity-limited in humans.
Limits
This is an in vitro assay utilizing pooled liver fractions; it does not measure in vivo pharmacokinetics, systemic tolerability, extrahepatic metabolism, or clinical outcomes in living human participants.
Cited by
- supports 1,3-butanediol is metabolized in the liver to form beta-hydroxybutyrate.