Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate

Elevation of the plasma levels of (<i>S</i>)-lactate (Lac) and/or (<i>R</i>)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between (<i>S</i>)-lactate and the BHB-precursor (<i>R</i>)-1,3-butanediol in the form of a simple ester referred to as <b><i>LaKe</i></b>. We show that <b><i>LaKe</i></b> can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of <b><i>LaKe</i></b>, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound <i>N</i>-L-lactoyl-phenylalanine (Lac-Phe).