Comparison of Valproic acid Clearance between Epileptic Patients and Patients with Acute Mania

Document Type: Original Article


1 Pharmaceutical Research Centre and School of Pharmacy, Department of Pharmacodinamy and Toxicology, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

2 Department of Neurology, Faculty of Medicine, Ghaem Hospital, MUMS, Mashhad, Iran

3 Department of Medicinal Chemistry, Pharmaceutical Research Centre and School of Pharmacy, MUMS, Mashhad, Iran

4 Department of Pharmaceutics, School of Pharmacy, Ahwaz University of Medical Sciences, Ahwaz, Iran

5 Department of Biotechnology, School of Pharmacy, MUMS, Mashhad, Iran


The purpose of this study was assessment of the influence of acute manic phase on the steady state pharmacokinetics of valproic acid (VPA) in bipolar patients in comparison with those of epileptic patients. Materials and Methods
Ninteen acutely manic and 25 epileptic patients who fulfilled inclusion and exclusion criteria were entered in this prospective study. Blood samples were collected at trough time in steady state and plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). VPA apparent oral clearance (CL/F) values were calculated in each patient and were compared between groups. As VPA clearance is affected by different factors such as age, total body weight, VPA dosage and the use of concurrent medications, all of these confounding factors were made similar in both groups.
Comparison between two groups showed that CL/F values in acutely manic patients were significantly higher than epileptic patients (10.35±5.77 vs. 7.70±2.63 ml/kg/h, P= 0.047).
Acutely manic patients require more VPA dosage to achieve serum concentrations in comparison with those found in epileptic patients. It may be suggested that this increased VPA clearance in acute manic phase may be related to abnormalities in membrane transport systems that may affect on cellular uptake of the drug and its volume of distribution. Since our study is a preliminary investigation in this field, further detailed pharmacokinetic study in acute manic patients are warranted to confirm results of this study.


1. Evans WE, Schentag JJ, Jasko WJ. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 3rd ed. Lippincott Williams & Wilkins; 1992.

2. Dipiro JT, Talbert RI, Yee GC, Matzke GR, Wells BG, Posy LM. Pharmacotherapy. 6th ed. New york: Mc Graw- Hill; 2011.

3. Coulter DL, Wu H, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980; 244:785-788.

4. Redenbaugh JE, Sato S, Penry JK. Sodium valproate: Pharmacokinetics and effectiveness in treating intractable seizures. Neurology 1980; 30:1-6.

5. DeVane CL. Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003; 37:25-42.

6. Lagace DC, O'Brien WT, Gurvich N, Nachtigal MW, Klein PS. Valproic acid: How it works. Or not. Clin Neurosci Res 2004; 4:215-225.

7. Reith DM, Andrews J, McLaughlin D. Valproic acid has temporal variability in urinary clearance of metabolites. Chronobiol Int 2001; 18:123-129.

8. Jiang Z, Zhang J, Liao HM, Tang JW, Peng QL. Influence of age, body weight and dose on sodium valproate plasma concentrations in children with epilepsy. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10:325-328.

9. Mohammadpoor AH, Ghaeli P, Sadray S, Noroozian M, Forooghipoor M, Rezaee S. Comparison of carbamazepine clearance between epileptic patients and patients with acute mania. Daru 2004; 12:141-145.

10.Perry PJ, Alexander B, Liskow BI. Psychotropic Drug Handbook. 7th ed. Washington: American Psychiatric Press; 1997.

11.Mokhber N, Lane CJ, Azarpazhooh MR, Salari E, Fayazi R, Shakeri MT, et al. Anticonvulsant treatments of dysphoric mania: a trial of gabapentin, lamotrigine and carbamazepine in Iran. Neuropsychiatr Dis Treat 2008;


12.Goodwin FK, Jamison KR. Biochemical and pharmacological studies. In: Goodwin FK, Jamison KR, editors. Newyork: Oxford University Press; 1990.

13.Janicak PG, Davis GM, S.H. P, F.J. A. Treatment with moodstabilizer.2nd ed.Baltimor: Williams &Wilkins; 1997.

14.Birnbaum AK, Hardie NA, Conway JM, Bowers SE, Lackner TE, Graves NM, et al. Valproic acid doses, concentrations, and clearances in elderly nursing home residents. Epilepsy Res 2004 ; 62:157-162.

15.Dipiro JT, Talbert RI, Yee GC, Matzke GR, Wells BG, Posy LM. Pharmacotherapy. 5th ed. New york: Mc Graw- Hill; 2005.

16.Nathan KL, Musselman DL, Schatzberg AF, Nemeroff CB. Biology of mood disorders. In: Schatzberg AF, Nemeroff CB, editors. Washington: American Psychiatric Press; 1995.

17.Shargel L, Yu BC. Applied Biopharmaceutics and Pharmacokinetics. 4th ed. New york: Prentice - Hall International Inc; 1999.