A 14C-leucine absorption, distribution, metabolism and excretion (ADME) study in adult Sprague–Dawley rat reveals β-hydroxy-β-methylbutyrate as a metabolite

“…The simplest explanation is that the N-acetyl-L-leucine is rapidly converted to L-leucine and utilized in metabolism. Rapid utilization and metabolism of L-leucine is consistent with the results of a study using stable isotope-labelled leucine itself upon oral administration [42]. Moreover, our inability to detect metabolites is consistent with the disappearance of N-acetyl-L-leucine though metabolism to L-leucine, which would be undetectable on the background of endogenous L-leucine.…”

“…Based on previous studies and our current results, we propose a mechanism of action of N -acetyl-leucine in which it is taken up and distributed by anion transporters, primarily MCT1. From the l -enantiomer, the l -leucine will be expected to be mostly utilized in the cell that deacetylates it, based studies on the uptake and utilization of 14 C- l -leucine 56 , with the important exception of the liver, which in contrast to all other amino acids does not metabolize leucine, but rather secretes it into the circulation for the use by other tissues, particularly skeletal muscle and the central nervous system 57 . MCT1-mediated uptake of N -acetyl- l -leucine provides a way to bypass the easily saturable uptake via LAT1 to deliver more leucine to tissues.…”

“…Likewise, the possibility that metabolites of leucine or amino acids other than leucine contribute to perturbed glucose uptake upon exogenous leucine administration cannot be excluded. It is widely acknowledged that the bolus administration of leucine results in increased formation of leucine metabolites (Lee et al 2015) and a reciprocal fall in plasma concentrations of the other branched chain amino acids (Matsumoto et al 2014). Notably, both the leucine metabolite α-ketoisocaproate and the branched chain amino acid isoleucine have been shown to stimulate increased glucose uptake in muscle (Doi et al 2007;Nishitani et al 2002) and cultured myotubes (Doi et al 2003).…”