Befuddled by Aspirin

Fatal Forty DDI: aspirin, valproic acid, protein binding
  • Melisa N. Weingarten
  • Juraj Sprung
  • Toby N. Weingarten


This case discusses dual pharmacokinetic drug–drug interactions that occur with coadministration of valproic acid and aspirin. There is mutual plasma-protein–binding displacement that will increase free valproic acid. Also, valproic acid is a substrate of mitochondrial β-oxygenase and aspirin is an inhibitor of mitochondrial ß-oxygenase.


Pharmacokinetic distribution Metabolism Aspirin Valproate Valproic acid Toxicity Free fraction Mitochondrial ß-oxidation Hypoalbuninemia Plasma proteins Protein binding Oxygenase 


  1. 1.
    Klotz U, Antonin KH. Pharmacokinetics and bioavailability of sodium valproate. Clin Pharmacol Ther. 1977;21:736–43.PubMedGoogle Scholar
  2. 2.
    DeVane CL. Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull. 2003;37 Suppl 2:25–42.PubMedGoogle Scholar
  3. 3.
    Ali MA, Routh JI. The protein binding of acetylsalicylic acid and salicylic acid. Clin Chem. 1969;15:1027–38.PubMedGoogle Scholar
  4. 4.
    Farrell K, Orr JM, Abbott FS, et al. The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children. J Pediatr. 1982;101:142–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Orr JM, Abbott FS, Farrell K, et al. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther. 1982;31:642–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology. 1987;37:1392–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Sandson NB, Marcucci C, Bourke DL, et al. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. Am J Psychiatry. 2006;163:1891–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Van den Branden C, Roels F. Peroxisomal beta-oxidation and sodium valproate. Biochem Pharmacol. 1985;34:2147–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Abbott FS, Kassam J, Orr JM, et al. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther. 1986;40:94–100.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Melisa N. Weingarten
    • 1
  • Juraj Sprung
    • 2
  • Toby N. Weingarten
    • 2
  1. 1.Patient EducationMayo ClinicRochesterUSA
  2. 2.Department of AnesthesiologyMayo ClinicRochesterUSA

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