A randomized, open-label, cross-over pilot study investigating metabolic product kinetics of the palatable novel ketone ester, bis-octanoyl (R)-1,3-butanediol, and bis-hexanoyl (R)-1,3-butanediol ingestion in healthy adults

• Published in: Toxicology research and application 2023-08, Vol.7
• Main Authors: Stubbs, Brianna J, Cook, Chad, Blonquist, Traci M, Taggart, Kristen, Beckman, Dawn, Kruger, Claire, Conze, Dietrich, Boileau, Amy C
• Format: Article
• Language: English
• Subjects: Acceptability; Adults; Blood plasma; Butanediol; Consumption; Esterases; Esters; Gastrointestinal system; Gastrointestinal tract; Hexanoic acid; Ingestion; Ketones; Labels; Metabolism; Metabolites; Octanoic acid; Plasma
• ISSN: 2397-8473; 2397-8473
• DOI: 10.1177/23978473231197835

Introduction Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel, palatable ketone ester that, when consumed, is hydrolyzed in the gastrointestinal tract into octanoic acid (OCT) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Metabolism of BO-BD is hypothesized to be similar to bis-hexanoyl (R)-1,3-butanediol (BH-BD), apart from release of octanoic acid instead of hexanoic acid (HEX). Methods As part of the safety assessment for BO-BD a randomized, cross-over, open-label study in middle-aged, healthy adults (n = 12) was undertaken to provide a qualitative comparison of plasma BHB, OCT, HEX and BDO concentrations for 8 h following consumption of 12.5 or 25 g of BO-BD and 12.5 g of BH-BD. Results All study products increased plasma BHB and BDO up to 4 h post-consumption. BH-BD increased HEX, whereas BO-BD increased OCT. All kinetic parameters for BHB and BDO were similar between 12.5 g servings of BH-BD and BO-BD while Cmax and AUC for OCT were higher following 12. 5 g servings of BO-BD as compared to HEX with 12.5 g of BH-BD. All metabolites returned to baseline by 8 h post-consumption. BHB, BDO and OCT Cmax and AUC were increased with serving size of BO-BD from 12.5 to 25 g. Sensory acceptability scores of BO-BD were significantly higher than for BH-BD. An in vitro hydrolysis experiment using human blood plasma further confirmed that plasma esterases possess the ability to break down the novel ketone esters into BDO, and OCT or HEX. Discussion The two novel ketone ester molecules exhibit similar metabolic breakdown to BHB and BDO and result in transiently higher concentrations of the plasma fatty acids, OCT and HEX, in vivo. Conclusions Given the similar ketone delivery with greater acceptability, BO-BD may offer a more broadly translatable tool to induce physiologic ketosis than BH-BD.