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Unit Code 81771:
Valproic Acid, Free and Total, Serum

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Useful For

Monitoring therapy

 

Assessing compliance

 

Evaluating potential toxicity

Clinical Information

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 85-90% 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.

Reference Values

TOTAL

      Therapeutic concentration

             40 ug/mL (trough)

             100 ug/mL (peak)

      Toxic concentration: > or =120 ug/mL

FREE

      Therapeutic concentration: 4-15 ug/mL

      Toxic concentration: >15 ug/mL

Interpretation

The generally acceptable range for total valproic acid used as a

reference to guide its therapy is 40-100 ug/mL. The corresponding

range of free valproic acid concentration for clinical reference is

4-15 ug/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

Specimens subjected to significant heat or other factors that

could cause protein denaturation would demonstrate an artificially

increased free valproic acid.

Clinical Reference

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

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