Valproic Acid, Free and Total, Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Valproate (Depakote/Depakene valproic acid) is an effective medication for absence seizures, generalized tonic-clonic seizures, and partial seizures, when administered alone or in conjunction with other antiepileptic agents.
The valproic acid that circulates in blood is 85% to 90% protein-bound under normal circumstances. In uremia or during concomitant therapy with other drugs that are highly protein-bound (such as phenytoin), valproic acid is displaced from protein, resulting in a higher free fraction of the drug circulating in blood.
Since neurologic activity and toxicity of valproic acid are directly related to the unbound fraction of drug, adjustment of dosage based on knowledge of the free valproic acid concentration may be useful in the following situations: concomitant use of highly protein-bound drugs (usually >80% bound), hypoalbuminemia, pregnancy, renal or hepatic failure, and in the elderly. In these situations, the total valproic acid concentration in the blood may underestimate the disproportionately higher free valproic acid fraction.
Evaluating potential toxicity
The generally acceptable range for total valproic acid used as a reference to guide its therapy is 40 mcg/mL to 100 mcg/mL. The corresponding range of free valproic acid concentration for clinical reference is 4 mcg/mL to 15 mcg/mL.
Low free valproic acid concentration relative to these ranges may suggest inadequate dosing, while, a high free valproic acid concentration may be associated with toxic effects.
Because the concentration of valproic acid fluctuates considerably depending on the time from last dose, interpretation of the clinical significance of the valproic acid concentration must take into consideration the timing of the blood specimen. For this reason, 2 collections are sometimes made to assess the trough and peak concentrations.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Specimens subjected to significant heat or other factors that could cause protein denaturation would demonstrate an artificially increased free valproic acid.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Therapeutic concentration: 40 (trough)-100 (peak) mcg/mL
Toxic concentration: > or =120 mcg/mL
Therapeutic concentration: 4-15 mcg/mL
Toxic concentration: >15 mcg/mL
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Cloyd JC, Fischer JH, Kriel RL, Kraus DM: Valproic acid pharmacokinetics in children: Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 1993;53:22-29
2. Wagner ML, Graves NM, Leppik IE, et al: The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994;56:494-502
3. Dasgupta A, Volk A: Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit 1996;18:284-287