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

Lee, Anthony J.; Beno, David W. A.; Zhang, Xiaolin; Shapiro, Robin; Mason, Mark; Mason-Bright, Tanita; Surber, Bruce W.; Edens, Neilé K.

doi:10.1007/s00726-015-1920-6

Cited by 17 publications

(12 citation statements)

References 37 publications

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“…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.…”

Section: Stereoisomer Effects Manifested By Tissue Uptake and Metabolismsupporting

confidence: 87%

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

et al. 2020

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The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine). The results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (C max) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (k e and T 1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyl-leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the Lenantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of only N-acetyl-L-leucine.

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Section: Stereoisomer Effects Manifested By Tissue Uptake and Metabolismsupporting

confidence: 87%

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

et al. 2020

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Leucine and mTORc1 act independently to regulate 2-deoxyglucose uptake in L6 myotubes

et al. 2020

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Chronic mTORc1 hyperactivation via obesity-induced hyperleucinaemia has been implicated in the development of insulin resistance, yet the direct impact of leucine on insulin-stimulated glucose uptake in muscle cells remains unclear. To address this, differentiated L6 myotubes were subjected to various compounds designed to either inhibit mTORc1 activity (rapamycin), blunt leucine intracellular import (BCH), or activate mTORc1 signalling (3BDO), prior to the determination of the uptake of the glucose analogue, 2-deoxyglucose (2-DG), in response to 1 mM insulin. In separate experiments, L6 myotubes were subject to various media concentrations of leucine (0-0.8 mM) for 24 h before 2-DG uptake in response to insulin was assessed. Both rapamycin and BCH blunted 2-DG uptake, irrespective of insulin administration, and this occurred in parallel with a decline in mTOR, 4E-BP1, and p70S6K phosphorylation status, but little effect on AKT phosphorylation. In contrast, reducing leucine media concentrations suppressed 2-DG uptake, both under insulin-and non-insulin-stimulated conditions, but did not alter the phosphorylation state of AKT-mTORc1 components examined. Unexpectedly, 3BDO failed to stimulate mTORc1 signalling, but, nonetheless, caused a significant increase in 2-DG uptake under non-insulin-stimulated conditions. Both leucine and mTORc1 influence glucose uptake in muscle cells independent of insulin administration, and this likely occurs via distinct but overlapping mechanisms.

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“…The majority of α-KIC is transported to the liver where it undergoes irreversible oxidation for the production of the energy substrates acetoacetate and acetyl Co-A [10] . However, in both muscle and liver, some α-KIC is metabolized via KIC-dioxygenase (more commonly called 4-hydroxyphenylpyruvate dioxygenase; HPD) to produce β-hydroxy-β-methylbutyrate (HMB) [10] , [11] , with a recent study in rats showing active conversion of 14 C-leucine to HMB in vivo , with appearance of 14 C-HMB in both plasma and urine following an oral dose of 14 C Leucine [12] . Of all the leucine metabolites formed, the efficacy of HMB in producing anabolic/anti-catabolic effects is perhaps most compelling.…”

Section: Introductionmentioning

confidence: 99%

Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism

et al. 2018

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

Cited by 17 publications

References 37 publications

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

Leucine and mTORc1 act independently to regulate 2-deoxyglucose uptake in L6 myotubes

Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism

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