Isobutyryl-L-carnitine
(Synonyms: 异丁酰-L-肉碱) 目录号 : GC30728An acylcarnitine
Cas No.:25518-49-4
Sample solution is provided at 25 µL, 10mM.
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Isobutyryl-L-carnitine is a natural 4-carbon acylcarnitine that is involved in fatty acid oxidation and organic acid metabolism.1 Elevated levels of isobutyryl-L-carnitine are associated with isobutyryl-CoA dehydrogenase deficiency.2,3
1.Turer, A.T., Stevens, R.D., Bain, J.R., et al.Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusionCirculation119(13)1736-1746(2009) 2.Koeberl, D.D., Young, S.P., Gregersen, N., et al.Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screeningPediatr. Res.54(2)219-223(2003) 3.Rinaldo, P., Cowan, T.M., and Matern, D.Acylcarnitine profile analysisGenet. Med.10(2)151-156(2008)
Cas No. | 25518-49-4 | SDF | |
别名 | 异丁酰-L-肉碱 | ||
Canonical SMILES | CC(C)C(O[C@H](CC([O-])=O)C[N+](C)(C)C)=O | ||
分子式 | C11H21NO4 | 分子量 | 231.29 |
溶解度 | DMSO: 250 mg/mL (1080.89 mM); Water: 125 mg/mL (540.45 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 4.3236 mL | 21.6179 mL | 43.2358 mL |
5 mM | 0.8647 mL | 4.3236 mL | 8.6472 mL |
10 mM | 0.4324 mL | 2.1618 mL | 4.3236 mL |
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Characterization and subcellular localization of L-[3H] carnitine binding sites in rat brain
In the present study, we investigated the existence of a binding site for L-carnitine in the rat brain. In crude synaptic membranes, L-[3H]carnitine bound with relatively high affinity (KD = 281 nM) and in a saturable manner to a finite number (apparent Bmax value = 7.3 pmol/mg of protein) of binding sites. Binding was reversible and dependent on protein concentration, pH, ionic strength, and temperature. Kinetic studies revealed a Koff of 0.018 min-1 and a Kon of 0.187 x 10(-3) min-1 nM-1. Binding was highest in spinal cord, followed by medulla oblongata-pons > or = corpus striatum > or = cerebellum = cerebral cortex = hippocampus = hypothalamus = olfactory bulb. L-[3H]Carnitine binding was stereoselective for the L-isomers of carnitine, propionylcarnitine, and acetylcarnitine. The most potent inhibitor of L-[3H]carnitine binding was L-carnitine followed by propionyl-L-carnitine. Acetyl-L-carnitine and isobutyryl-L-carnitine showed an affinity approximately 500-fold lower than that obtained for L-carnitine. The precursor gamma-butyrobetaine had negligible activity at 0.1 mM. L-Carnitine binding to rat crude synaptic membrane preparation was not inhibited by neurotransmitters (GABA, glycine, glutamate, aspartate, acetycholine, dopamine, norepinephrine, epinephrine, 5-hydroxytryptamine, histamine) at a final concentration of 0.1 mM. In addition, the binding of these neuroactive compounds to their receptors was not influenced by the presence of 0.1 mM L-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibitory action of isovaleryl-L-carnitine on proteolysis in perfused rat liver
Isovaleryl-l-carnitine inhibits the proteolysis induced by amino acid deprivation in the perfused rat liver to an extent equivalent, or, below 0.4 mM, even greater than that previously found for 1-leucine (Ref. 1). Also the typical concentration-response curve previously found for leucine (Ref. 1) is mimicked by isovaleryl-l-carnitine. The maximum inhibition (approximately 50% of the control) occurred for both l-leucine and isovaleryl-l-carnitine above 0.8 mM. Only at these high concentrations also 1-carnitine and isobutyryl-l-carnitine exhibit a significant, albeit lower, degree of inhibition. The possible mechanism of this proteolysis inhibition is discussed.
A Multiplexed HILIC-MS/HRMS Assay for the Assessment of Transporter Inhibition Biomarkers in Phase I Clinical Trials: Isobutyryl-Carnitine as an Organic Cation Transporter (OCT1) Biomarker
There is a growing interest in using endogenous compounds as drug transporter biomarkers to facilitate drug-drug interaction (DDI) risk assessment in early phase I clinical trials. Compared to other drug transporters, however, no valid biomarker for hepatic organic cation transporter (OCT) 1 has been described to date. The present work represents the first report of an endogenous compound, isobutyryl-l-carnitine (IBC), as a potential clinical OCT1 biomarker for DDI assessment. A hydrophilic interaction chromatography (HILIC)-mass spectrometry/high resolution mass spectrometry (MS/HRMS) assay with a simple sample preparation method was developed. The assay is capable of simultaneously quantifying multiple endogenous compounds, including IBC, thiamine, N1-methylnicotinamide (1-NMN), creatinine, carnitine, and metformin, which is a probe for OCT1 and OCT2 and MATE1 and MATE2K (multidrug and toxin extrusion proteins) in clinical studies. The HRMS assay was fit-for-purpose validated in human plasma and demonstrated good linearity, accuracy, and precision for all analytes. It was further applied to two phase I clinical trials to evaluate potential biomarkers for OCT1 and additional cation transporters (renal OCT2, MATE1, and MATE2K). The clinical data demonstrated that plasma IBC changes correlated well with in vitro data and supported its use as a liver OCT1 biomarker. The described HILIC-MS/HRMS assay can be used as a "biomarker cocktail" to simultaneously assess clinical DDI risk for the inhibition of OCT1/2 and MATEs in clinical studies with new drug candidates.
Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1
Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib. In addition, we found that dasatinib can inhibit hepatic OCT1 function in mice as evidenced from its ability to modulate levels of isobutyryl L-carnitine, a hepatic OCT1 biomarker identified from a targeted metabolomics analysis. These findings provide novel insight into the post-translational regulation of OCT1 and suggest that caution is warranted with polypharmacy regimes involving the combined use of OCT1 substrates and kinase inhibitors that target YES1.
Urinary metabonomic study of patients with acute coronary syndrome using UPLC-QTOF/MS
This urinary metabonomic study aimed to identify the potential metabolic biomarkers in acute coronary syndrome (ACS) patients. Ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) was used to analyze the urine samples from ACS patients and healthy controls. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to characterizing the endogenous metabolites and potential biomarker, respectively. Among twenty biomarkers that functioned in nine metabolic pathways, nine biomarkers were found up-regulated significantly, including of isobutyryl?l?carnitine, 3?methylglutarylcarnitine, cinnavalininate, l?tryptophan, 3?methyldioxyindole, palmitic acid, N4?acetylaminobutanal, 3?sulfino?l?alanine and S?adenosyl?l?homocysteine. The other eleven biomarkers were showed down-regulated, including of l?lactic acid, trigonelline, nicotinuric acid, l?alanine, d?alanyl?d?alanine, creatine, N4?acetylaminobutanoate, glutathionyl spermidine, 5?methoxytryptamine, kynurenic acid and xanthurenic acid. This study also implied that fatty acid metabolism, fatty acid β?oxidation metabolism, amino acid metabolism and TCA cycle played important roles in ACS. Therefore, urinary metabolomics may improve the diagnosis efficacy of ACS and make it more accurate and comprehensive for ACS diagnosis.