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From the National Institutes of Health (Dr. Marini), Bethesda, MD; the Department of Neurology (Dr. Zaret), University of Massachusetts Medical Center, Worcester, MA; and the Department of Pharmacy (Dr. Beckner), Barnes Hospital, St. Louis, MO.
Valproic acid (VPA) consistently and reproducibly elevates arterial ammonia in rats injected with an amino acid load. The extent of the hyperammonemia is dependent on the dose of VPA injected or VPA plasma concentration and the amino acid dose. Bilaterally nephrectomized rats injected with VPA and an amino acid load also develop hyperammonemia, which overall approximates 75% of that achieved in non-nephrectomized animals. In non-nephrectomized animals injected with an amino acid load, valproic acid produces a marked reduction in baseline and activated hepatic mitochondrial carbamyl phosphate synthetase I activity. Our results suggest that VPA-induced hyperammonemia after an amino acid load results from inhibition of hepatic intramitochondrial citrullinogenesis with only a limited contribution from the kidneys.
Address correspondence and reprint requests to Dr. Marini, Public Health Service, National Institutes of Health, Building 36, Room 3C-07, Bethesda, MD 20205.
Supported by grants from the Department of Medicine, UMMC, and from Abbott Laboratories, North Chicago, IL.
Presented in part at the thirty-seventh annual meeting of the American Academy of Neurology, Dallas, TX, April 1985.
Received February 18, 1987. Accepted for publication in final form June 12, 1987.
This article has been cited by other articles:
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  E. Cheung, V. Wong, and C.-W. Fung Topiramate-Valproate--Induced Hyperammonemic Encephalopathy Syndrome: Case Report J Child Neurol, February 1, 2005; 20(2): 157 - 160. [Abstract] [PDF]
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 L. Mallet, S. Babin, and J. A Morais Valproic Acid-Induced Hyperammonemia and Thrombocytopenia in an Elderly Woman Ann. Pharmacother., October 1, 2004; 38(10): 1643 - 1647. [Abstract] [Full Text] [PDF]
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 D. Feil, K. Chuang, and D. L. Sultzer Valproate-Induced Hyperammonemia as a Cause of Altered Mental Status Am J Geriatr Psychiatry, August 1, 2002; 10(4): 476 - 478. [Abstract] [Full Text] [PDF]
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 M Oechsner, C Steen, H J Sturenburg, and A Kohlschutter Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency J. Neurol. Neurosurg. Psychiatry, May 1, 1998; 64(5): 680 - 682. [Abstract] [Full Text] [PDF]
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S. Altunbsak, V. Baytok, M. Tasouji, O. Herguner, R. Burgut, and L. Kayrin Asymptomatic Hyperammonemia in Children Treated With Valproic Acid J Child Neurol, October 1, 1997; 12(7): 461 - 463. [PDF]
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D. L. Coulter Carnitine Deficiency in Epilepsy: Risk Factors and Treatment J Child Neurol, November 1, 1995; 10(2_suppl): 2S32 - 2S39. [Abstract] [PDF]
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D. L. Coulter Review Article: Carnitine, Valproate, and Toxicity J Child Neurol, January 1, 1991; 6(1): 7 - 14. [Abstract] [PDF]
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