Serum Carnitine During Valproic Acid Therapy

Laub, M.; Paetzke-Brunner, I.; Jaeger, G E

doi:10.1111/j.1528-1157.1986.tb03584.x

Cited by 105 publications

(54 citation statements)

References 24 publications

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“…VPA causes decreased serum levels of carnitine. 7,8 Deficiency of carnitine results in diminished mitochondrial function, with inhibition of the urea cycle in the liver. 9 In a retrospective chart review, administration of L-carnitine was associated with reduced mortality in patients with severe VPA-induced hepatotoxicity.…”

Section: Treatmentmentioning

confidence: 99%

Valproate-associated Hyperammonemic Encephalopathy

Wadzinski¹,

Franks²,

Roane³

et al. 2007

The Journal of the American Board of Family Medicine

113

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The use of valproic acid (VPA) (also known as Depakote, Depakene, and others) frequently results in elevated plasma ammonia. In some people, hyperammonemia may be clinically significant, resulting in hyperammonemic encephalopathy, which may be severe. Valproic acid-induced hyperammonemic encephalopathy may occur in people with normal liver function, despite normal doses and serum levels of VPA. We describe 2 cases of valproic acid-induced hyperammonemic encephalopathy in patients with supratherapeutic VPA levels, although the condition has been described in people with normal VPA lev- Valproic acid (VPA) is effective in the treatment of seizure disorders, bipolar disorder, migraine headache prophylaxis, neuropathic pain, restless legs syndrome, dementia-related agitation, and social anxiety disorder, among other conditions. VPA has numerous drug interactions and toxicities; severe toxicities include hepatic damage, pancreatitis, teratogenicity, thrombocytopenia, and hyperammonemia. Here we depict 2 case reports of VPAinduced hyperammonemic encephalopathy (VHE), both occurring in patietns with no history of underlying liver disease. In one instance, the patient was able to function, but with significant cognitive limitations. In the second case, the patient was comatose. Both of the patients we describe also had supratherapeutic VPA levels, but VHE is a welldocumented potential complication of the use of VPA in the medical literature, and it may occur in people with normal VPA levels.1 Because of the wide spectrum of symptoms associated with VHE, physicians should consider hyperammonemia in the differential diagnosis of any patient taking VPA who shows changes in behavior, cognition, or orientation. Case ReportsCase 1 A 51-year-old woman was transferred from a psychiatric hospital to an emergency department to evaluate the recent deterioration in her mental status. She had been admitted to the psychiatric hospital for an exacerbation of posttraumatic stress disorder and was placed on extended-release VPA at 1,000 mg nightly. After 7 days of treatment she was no longer responsive to verbal stimuli. Her medical history was significant for migraine headaches, posttraumatic stress disorder, and major depression. Her medications included topiramate (for migraine prophylaxis), quetiapine, and VPA. In the emergency department, she was nonresponsive to verbal or painful stimuli; her vital signs were normal. Her pupils were equal at 5 mm and her ammonia level was 232 mol/L (N ϭ 10 to 47); her VPA level was 145 g/mL (N ϭ 50 to 100); and aspartate aminotransferase and alanine aminotransferase were normal at 17 IU/L and 19 IU/L, respectively. The remainder of laboratory tests, including all liver tests, were normal. For the first 24 hours, the patient remained nonresponsive; her This article was externally peer reviewed.

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Section: Treatmentmentioning

confidence: 99%

Valproate-associated Hyperammonemic Encephalopathy

Wadzinski¹,

Franks²,

Roane³

et al. 2007

The Journal of the American Board of Family Medicine

113

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“…In valproate-treated mice, high levels of serum ammonia were seen in the face of normal free and esterified serum carnitine levels (3 1). Serum carnitine levels were normal in a child who developed hepatic dysfunction while receiving valproate, and carnitine treatment did not prevent liver failure (30).…”

Section: Discussionmentioning

confidence: 93%

“…From the presently available data, a role for carnitine deficiency in valproate-associated hepatotoxicity and possible beneficial effects of carnitine supplementation is not clear. There are reports of decreased levels of free carnitine in the plasma of epileptic children receiving valproate (27)(28)(29)(30). Ohtani et al (27) found that cotreatment of these children with carnitine returned the valproate-induced decrease of the plasma carnitine level and the elevation of the ammonia concentration to normal.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Adverse Effects of Valproic Acid on Ketogenesis and Liver Coenzyme A Metabolism by Cotreatment with Pantothenate and Carnitine in Developing Mice: Possible Clinical Significance

Thurston

Hauhart

1992

Pediatr Res

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ABSTRACT. Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of B-oxidation. The present study shows for the first time that in developing mice, when pantothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the /3-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of Boxidation and other CoA-and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase. (Pediatr Res 31: 419-423, 1992) The new anticonvulsant drug, valproic acid (2-n-propylpentanoic acid, 2-n-propylvaleric acid), is particularly effective in the treatment of the types of seizures peculiar to infants and young children: infantile myoclonic spasms, febrile seizures, and petit ma1 (absence) (reviewed in Ref. 1). Yet this is the age group that is most susceptible to the hepatotoxic effects of the drug, particularly if the children have organic brain damage and are also receiving other anticonvulsant drugs (2). In a study of possible mechanisms of this complication, we found that valproate reduced the physiologic ketonemia of suckling mice (3, 4) and fasting epileptic children (5). In the livers of normal developing mice, valproate produced extraordinary decreases in the levels of free CoA, acetyl CoA, and free carnitine (4). Concomitantly, the concentration of medium-chain acyl CoA esters [including valproyl CoA and its metabolites (6)] increased some 6-to 7-fold (4). As in our normal developing mice, valproate also reduced plasma P-hydroxybutyrate levels and liver CoA and acetyl CoA levels in fasted adult rats (7, 8). In isolated adult rat hepatocytes, valproate inhibited oxidation of fatty acids and pyruvate, fatty acid synthesis, gluconeogenesis, ketogenesis, and ureagenesis (6, 7,9-11). In view of the 100 or so synthetic and catabolic enzyme reactions requiring CoA or acetyl CoA as substrates, cofactors, or activators, the above diverse ill effects of valproate on liver metabolism can largely be explained by sequestration of free CoA into nonmetabolized or poorly metabolized valproyl CoA and valpro...

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“…This results in carnitine depletion in human skin fibroblast [173]. Thus, VPA decreases level of carnitine in the blood [174]. …”

Section: Anti-epileptic Drug Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Serum Carnitine During Valproic Acid Therapy

Cited by 105 publications

References 24 publications

Valproate-associated Hyperammonemic Encephalopathy

Valproate-associated Hyperammonemic Encephalopathy

Amelioration of Adverse Effects of Valproic Acid on Ketogenesis and Liver Coenzyme A Metabolism by Cotreatment with Pantothenate and Carnitine in Developing Mice: Possible Clinical Significance

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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