Pharmacokinetics of valproic acid in patients with bipolar disorder

Abstract

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400–1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1–2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73 ± 11.96 µg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2 ± 6.39 h. Total plasma clearance was 0.095 ± 0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11 ± 0.05 l/kg. A positive correlation (r= 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 µg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.

Keywords

mania pharmacokinetics therapeutic range valproate

Get full access to this article

View all access options for this article.

References

American Psychiatric Association (1993) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

American Psychiatric Association (1994) Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 151: 1–36

Bowden C L , Janicak P G , Orsulak P (1996) Relation of serum valproate concentration to response in mania. Am J Psychiatry 153: 765–770

Dunner D L , Patrick V , Fieve R R (1977) Rapid cycling manic depressive patients. Compr Psychiatry 18: 561–566

Eadie M J , Heazlewood V , McKauge L , Tyrer J H (1983) Steady state valproate phamacokinetics during long term therapy. Clin Exp Neurol 19: 183–191

Gugler R , Unruh GE (1980) Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 5: 67–83

Gugler R , Schell M , Eichelbaum M , Froscher W , Schulz H U (1977) Disposition of valproic acid in man. Eur J Clin Pharmacol 12: 125–132

Klotz U , Antonin K H (1977) Pharmacokinetics of sodium valproate. Clin Pharmacol Therapeut 21: 736–743

McElroy S L , Keck P E , Pope H G et al. (1992) Valproate in the treatment of bipolar disorder: literature review and clinical guidelines. J Clin Psychopharmacol 12: 42–52

10.

McNamara J O (1996) Drugs effective in the therapy of the epilepsies. In Hardman J G , Limbird L E , Molinoff P B , Ruddon R W , Gilman A G (eds), Goodman and Gilman's the pharmacological basis of therapeutics, 9th edn, pp. 461–486. New York, McGraw-Hill

11.

Miljkovic B , Pokrajac M , Varagic V , Levic Z (1991) Single dose and steady state pharmacokinetics of valproic acid in adult epileptic patients. Int J Clin Pharmacol Res 11: 137–121

12.

Nitsche V , Mascher H (1982) The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia 23: 153–162

13.

Vasudev K , Goswami U , Kohli K (2000) Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder. Psychopharmacology 150: 15–23