On the Metabolism of Exogenous Ketones in Humans

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-ß-hydroxybutyrate (D-ßHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium ßHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of ßHB. Both drinks elevated blood D-ßHB concentrations (D-ßHB C_max: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-ßHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-ßHB and L-ßHB was <1.5% of the total ßHB ingested and was in proportion to the blood AUC. D-ßHB, but not L-ßHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-ßHB concentrations was determined in 16 participants. Food lowered blood D-ßHB C_max by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-ßHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-ßHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.