Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry☆
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Cited by (114)
Medical Monitoring and Diagnosis
2015, The Encyclopedia of Mass Spectrometry: Volume 9: Historical Perspectives, Part A: The Development of Mass SpectrometryHepatic toxicity of dronedarone in mice: Role of mitochondrial β-oxidation
2014, ToxicologyCitation Excerpt :This may be due to differences in metabolic pathways and toxicological mechanisms of these drugs. While dronedarone is mainly metabolized by CYP3A4 through debutylation (Dorian, 2010; Patel et al., 2009), valproic acid is metabolized mainly by conjugation, including also conjugation with carnitine (Millington et al., 1985; Murakami et al., 1996). Furthermore, oxidative metabolism of valproic acid is associated with toxic acidic metabolites (e.g., Δ2,4-diene valproic acid and other reactive metabolites), which can form carnitine esters and be excreted (Rettenmeier et al., 1985; Silva et al., 2001).
Anticonvulsant agents
2013, Drug-Induced Liver DiseaseEvaluation of valproate effects on acylcarnitine in epileptic children by LC-MS/MS
2011, Brain and DevelopmentCitation Excerpt :The concentration of valproylcarnitine was very low (maximum: 0.026 μM), and only trace amounts (below the limit of quantitation) were detected in a few samples, even in VPA-treated patients. On the basis of our findings and given that the urinary excretion of valproylcarnitine accounts for <1% of total acylcarnitine elimination in urine [21,22], the formation of valproylcarnitine alone is not sufficient to reduce carnitine concentrations at therapeutic doses of VPA. Werner et al. reported the increase of C8 during VPA treatment and assumed the C8 signal represented predominantly octanoylcarnitine [17].
The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: Relationship to blood carnitine status
2009, Epilepsy ResearchCitation Excerpt :Sequential formation of valproyl-CoA and valproylcarnitine leads to direct competitive inhibition of carnitine uptake at the transporter site as follows: (a) VPA causes competition between FC and ACs, including valproylcarnitine esters and short chain acylcarnitines at plasmalemmal high affinity carnitine transporter site. Because cellular energy demands remain constant utilization of fatty acids for energy needs, inhibition of β-oxidation of fatty acid caused by VPA and results in an increase in compensatory amino acid oxidation and a subsequent increase in the production of nitrogenous waste (Millington et al., 1985) and (b) valproyl-CoA (an esterified valproic acid) required for the formation of N-acetylglutamate, a powerful allosteric activator of carbamoyl phosphate synthetase I and critical to the short-term regulation of the synthesis of urea and nitrogen flux toward its appropriate metabolism. Therefore, a VPA-induced decrease in N-acetyl glutamate could reduce the synthesis of urea and produce a rise in ammonia (Coude et al., 1983; Laub, 1986), (4) VPA also causes impairment of renal absorption of carnitine (Warter et al., 1983).
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This study was supported in part by a grant from the National Reye's Syndrome Foundation, Bryan, OH; the Reye's Syndrome Research Fund — SFA (Duke University Medical Center) and RR-30 General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health, Bethesda, MD, USA.