Drug-Drug Interaction

VALPROIC ACID/SALICYLATES

MECHANISM OF ACTION
Multiple mechanisms appear to be involved. Salicylates may displace valproic acid from plasma protein binding sites. Salicylates may also affect the metabolism of valproate by increasing conjugation and decreasing oxidation of valproic acid.

DISCUSSION
In two studies involving 6 epileptic children taking valproic acid, concurrent aspirin led to an increase in serum valproic acid free fraction and an increased half-life. Renal clearance of free valproic acid was found to decrease.(1,2) In another study involving 5 children, concurrent valproic acid and aspirin resulted in a decrease in free valproic acid clearance although total valproic acid levels did not change significantly.(3) However, one study reported that the concurrent use of valproic acid and aspirin leads to an increased excretion of valproic acid and a decreased total salicylate excretion.(4)

CLINICAL EFFECTS
Concurrent use of salicylates may increase the unbound fraction of serum valproic acid concentration, resulting in toxicity.

SEVERITY LEVEL
3-Moderate Interaction: Assess the risk to the patient and take action as needed.

PATIENT MANAGEMENT
Patients receiving concurrent salicylate therapy should be observed for signs of valproic acid toxicity (e.g., ataxia, drowsiness, nystagmus, tremor). The dosage of valproic acid may need to be adjusted.

PREDISPOSING FACTORS
None determined.

REFERENCES

1. Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. .Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther 1982 May; 31(5):642-9.
2. Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic .Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 1986 Jul;40(1):94-100.
3. Farrell K, Orr JM, Abbott FS, Ferguson S, Sheppard I, Godolphin W, Bruni .Farrell K, Orr JM, Abbott FS, Ferguson S, Sheppard I, Godolphin W, Bruni J. The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children. J Pediatr 1982 Jul; 101(1):142-4.
4. Schobben F, Vree TB, van der Kleijn E. Pharmacokinetics, metabolism and .Schobben F, Vree TB, van der Kleijn E. Pharmacokinetics, metabolism and distribution of 2-N-propyl-pentanoate (sodium valproate) and the influence of salicylate comedication. In Meinardi, H. //Rowan, A. J. Advances in Epileptology Psychology, Pharmacotherapy and New Diagnostic Approaches. Amsterdam, Swets & Zeitlinger B. V. 1978;271-7.
5. Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity .Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987 Aug;37(8):1392-4.
6. Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R. An interaction .Sandson NB, Marcucci C, Bourke DL, Smith-Lamacchia R. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. Am J Psychiatry 2006 Nov; 163(11):1891-6.
7. Addison RS, Parker-Scott SL, Eadie MJ, Hooper WD, Dickinson RG. .Addison RS, Parker-Scott SL, Eadie MJ, Hooper WD, Dickinson RG. Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers. Eur J Clin Pharmacol 2000 Dec; 56(9-10):715-21.
8. Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH, .Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH, Baillie TA. Studies on the biotransformation in the perfused rat liver of 2-n- propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates. Drug Metab Dispos 1985 Jan-Feb;13(1):81-96.
9. Fleitman JS, Bruni J, Perrin JH, Wilder BJ. Albumin-binding interactions .Fleitman JS, Bruni J, Perrin JH, Wilder BJ. Albumin-binding interactions of sodium valproate. J Clin Pharmacol 1980 Aug-Sep;20(8-9):514-7.