Valproic acid toxicokinetics: Serial hemodialysis and hemoperfusion

The toxicity and pharmacokinetic properties of a drug determine whether hem odialysis and/or hemoperfusion are indicated in acute intoxications. Valpro ic acid is considered unremovable by hemodialysis because of the high prote in binding of 90%-95%. A 27-year-old male with a history of seizures was ad mitted to the emergency room because of coma, hypernatriemia, and respirato ry failure caused by an intoxication with a large dose of valproic acid. At admission; the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (ther apeutic range: 50-100 mg/L (350-700 umol/L). The anion gap was 26 mmol/L (n ormal < 12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level s erial hemodialysis and hemoperfusion was performed. The first session was d one with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemo perfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the f irst hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective b ecause of saturation of the column. In conclusion, the toxicokinetics of va lproate are quite different from the pharmacokinetics at therapeutic levels . The anion gap and protein binding are important parameters in toxicokinet ics.