Preparation and\nPreclinical Characterization of a\nSimple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate

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