The Effect of Carnitine on the Metabolism of Valproic Acid in Epileptic Patients.

Sakemi, Kikuo; Hayasaka, Kiyoshi; Tahara, Marie; Sanada, Yukiaki; Takada, Goro

doi:10.1620/tjem.167.89

Cited by 9 publications

(3 citation statements)

References 10 publications

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“…Curiously, evidence to support effectiveness of L-carnitine in improving VPA poisoning is still poor. Reduction in t 1/2 was attributed to L-carnitine in eight non-overdosed long-term VPA-treated patients (9.5 h versus 12 h, P < 0.05) [ 26 ]; however, t 1/2 in this study were shorter compared to ours. A Romanian randomized controlled trial including 62 VPA-poisoned patients admitted to the ICU (28 treated versus 34 non-treated patients with L-carnitine 1,800 mg/day for 3 days) reported that L-carnitine reduced plasma VPA levels and facilitated the decrease in plasma ammonia concentrations [ 27 ].…”

Section: Discussionmentioning

confidence: 51%

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships

Nguyên

Chevillard

Gouda

et al. 2022

Ann. Intensive Care

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Background Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. Results Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32–47]) (median [25th–75th percentiles]; SOFA score, 4 [1–6]) were included. The presumed VPA ingested dose was 15 g [10–32]. Plasma VPA concentration on admission was 231 mg/L [147–415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7–4.9]) and hyperammonemia (127 mmol/L [92–159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [$$E={E}_{0}\times {e}^{k\cdot C}$$ E = E 0 × e k · C ; with baseline E0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2–2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. Conclusions VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.

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Section: Discussionmentioning

confidence: 51%

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships

Nguyên

Chevillard

Gouda

et al. 2022

Ann. Intensive Care

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“…Supplementation with L-carnitine leads to normalization of the half-life of VPA. Furthermore, L-carnitine supplementation doesn't seem to shorten the half-life of VPA, which could lead to sub therapeutic levels and subsequent seizures [22]. Animal models also indicate that L-carnitine supplementation has no impact on seizure control in the presence of other AED [23], while leading to increased VPA concentrations within the brain [24].…”

Section: Discussionmentioning

confidence: 99%

Levocarnitine induced seizures in patients on valproic acid: A negative systematic review

Zeiler

Sader

Gillman

et al. 2016

Seizure

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There is no literature available to support claims of L-carnitine induced seizures during supplementation in patients on VPA therapy for seizures. This contradicts quoted, but not referenced, concerns on the product monograph. In patients suffering from hypocarnitinemia or hyperammonemic encephalopathy while on VPA, L-carnitine supplementation can be considered knowing there is no data to support seizure propagation or induction with administration of this supplement.

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“…Kay et al(1986) and Hjelm et al (1986) have reported cases in which occult metabolic disorders were revealed during the administration of VPA. In other studies, L-carnitine supplementation was tried for normalization of carnitine deficiency in VPA-treated patients (Ohtani et al 1982;Sakemi et al 1992). …”

Section: Discussionmentioning

confidence: 99%

Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug.

Ito

Sugiyama

Kobayashi

et al. 1995

Tohoku J. Exp. Med.

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We investigated the influence on mitochondrial functions in carnitine deficiency caused by short-term treatment of cefterampivoxil (CFTM-PI) which is one of pivaloyloxymethyl-esterified antibiotics in adult volunteers and diseased children. Administration of CFTM-PI caused hypocarnitinemia in all cases, and we observed a significant elevation of blood ammonia levels compared with those after its withdrawal in diseased children. A significant negative correlation was found between the levels of serum free carnitine and blood ammonia, and a positive correlation was observed between serum carnitine and blood glutamine levels in all adult samples and samples during administration in diseased children. Our data suggest that these antibiotic medications affect the mitochondrial function even in a short-term treatment and that L-carnitine supplementation would be necessary for patients treated with CFTM-PI. carnitine deficiency; pivalic acid; hyperammonemia Carnitine, a cofactor for mitochondrial /l-oxidation of long-chain fatty acids, is essential for energy production and enhances the excretion of accumulated acyl-CoA to regulate the intramitochondrial CoA/acyl-CoA ratio. The systemic carnitine deficiency noted in various disorders can cause hypoketotic hypoglycemia, cardiomyopathy and Reye-like syndrome because functions of carnitine are insufficient.Some oral antibiotics in general use are esterified with pivaloyloxymethyl moiety in order to increase the intestinal absorption rate. This group of antibi-

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The Effect of Carnitine on the Metabolism of Valproic Acid in Epileptic Patients.

Cited by 9 publications

References 10 publications

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships

L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships

Levocarnitine induced seizures in patients on valproic acid: A negative systematic review

Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug.

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