Valproic Acid (Total+Free)

Valproic Acid (Total+Free) testing is used for therapeutic drug monitoring of valproate (valproic acid; divalproex sodium) to establish an effective concentration and dosing schedule, evaluate adherence, and minimize toxicity. It is applied across generalized epilepsies—such as typical absence, myoclonic, and generalized tonic–clonic seizures—as well as partial and mixed seizure types. Measuring both total and free drug is helpful when protein binding or metabolism changes may cause discordance between fractions. The test also supports assessment of suspected overdose, monitoring during pregnancy and other physiologic shifts, and dose adjustment when coadministered antiepileptic drugs are started or discontinued. Trough sampling collected at a consistent time is commonly preferred for interpretation.

Valproic acid enhances inhibitory neurotransmission primarily through inhibition of GABA transaminase, increasing central gamma-aminobutyric acid (GABA) levels and lowering neuronal excitability. It is active across multiple epilepsy phenotypes and is also used in bipolar disorder, migraine prophylaxis, and additional neurologic and psychiatric settings. After oral administration, absorption is rapid and nearly complete. Protein binding is high and becomes saturable within the therapeutic range. Biotransformation is hepatic, occurring via conjugation and mitochondrial beta-oxidation. Therapeutic monitoring improves efficacy and safety because pharmacokinetics are nonlinear and dose-related adverse effects—such as weight gain, nausea, tremor, dizziness, pancreatitis, hepatotoxicity, and central nervous system depression—rise with higher exposure; severe toxicity and coma are uncommon but can occur with substantial overdose. Sampling strategy is determined by the treating clinician; consistently timed trough levels are commonly obtained, and paired trough/peak measurements may be used in select scenarios.