European Journal of Clinical Pharmacology

, Volume 74, Issue 5, pp 675–677 | Cite as

Subtherapeutic valproic acid plasma concentrations under concomitant dipyrone therapy in an epilepsy patient—a case report

  • Benedict Morath
  • K. Green
  • M. Zaradzki
  • J. Heid
  • M. Karck
  • T. Hoppe-Tichy
Letter to the Editor

Case report

Valproic acid (VPA) is used as a broad anticonvulsant in the treatment of general and focal epilepsy and as maintenance therapy in bipolar disorder [1, 2]. Its effects are mediated by a blockage of voltage-gated sodium channels and additional mechanisms of action, which result in an increase of brain gamma butryric acid (GABA) concentrations and a blockage of T-type calcium currents [1]. VPA is metabolized by CYP2C9, CYP2A6, CYP2C19, and CYP2B6 [3, 4]. Due to highly variable plasma concentrations, therapeutic drug monitoring during valproate therapy is recommended with a target VPA plasma concentration (pcVPA) of 50 to 100 mg/l [5].

Dipyrone (DPR), also known as metamizole, is a pyrazolone derivative that is hydrolyzed to the active 4-methyl-amino-antipyrine and acts as a potent analgesic with spasmolytic properties [6]. In some European countries, it is widely used with about 175 million defined daily doses solely prescribed in Germany in 2014, but in several countries...


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent of the patient

The informed consent of the patient was obtained.


  1. 1.
    Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS drugs 16(10):669–694. CrossRefPubMedGoogle Scholar
  2. 2.
    Mahli GS, Adams D, Cahill CM, Dodd S, Berk M (2009) The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. Drugs 69(15):2063–2101. CrossRefGoogle Scholar
  3. 3.
    Fleming J, Chetty M (2005) Psychotropic drug interactions with valproate. Clin Neuropharmacol 28(2):96–101. CrossRefPubMedGoogle Scholar
  4. 4.
    Tan L, Yu JT, Sun YP, Ou JR, Song JH, Yu Y (2010) The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin Neurol Neurosurg 112(4):320–323. CrossRefPubMedGoogle Scholar
  5. 5.
    Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann P (2017) Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry.
  6. 6.
    Levy M, Zylber-Katz E, Rosenkranz B (1995) Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 28(3):216–234. CrossRefPubMedGoogle Scholar
  7. 7.
    European Medicines Agency. List of nationally authorised medicinal products: active substance: metamizole. Accessed 22.09.2017
  8. 8.
    Schwabe U, Paffrath D, Böger RH, Schmidt G (2015) Arzneiverordnungsreport 2015. Springer, Berlin Heidelberg. CrossRefGoogle Scholar
  9. 9.
    Zylber-Katz E, Granit L, Levy M (1985) Plasma protein binding of dipyrone metabolites in man. Eur J Clin Pharmacol (1985) 29 (1): 67–71. doi:
  10. 10.
    Saussele T, Burk O, Blievernicht JK, Klein K, Nussler A, Nussler N, Hengstler JG, Eichelbaum M, Schwab M, Zanger UM (2007) Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin Pharmacol Ther 82(3):265–274. CrossRefPubMedGoogle Scholar
  11. 11.
    Qin WJ, Zhang W, Liu ZQ, Chen XP, Tan ZR, Hu DL, Wang D, Fan L, Zhou HH (2012) Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. Br J Clin Pharmacol 74(6):999–1004. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kiang TK, Ho PC, Anari MR, Tong V, Abbott FS, Chang TK (2006) Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol Sci 94(2):261–271. CrossRefPubMedGoogle Scholar
  13. 13.
    Martin-Facklam M, Drewe J, Haefeli WE (2000) Drug interactions with the cytochrome P-450 system. Dtsch Med Wochenschr 125 (3):63–67. doi:

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Benedict Morath
    • 1
    • 2
    • 3
  • K. Green
    • 1
    • 3
  • M. Zaradzki
    • 4
  • J. Heid
    • 5
  • M. Karck
    • 4
  • T. Hoppe-Tichy
    • 1
    • 3
  1. 1.Hospital PharmacyUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Cooperation Unit Clinical PharmacyHeidelberg UniversityHeidelbergGermany
  4. 4.Department of Cardiac SurgeryUniversity Hospital HeidelbergHeidelbergGermany
  5. 5.Department of Cardiology, Angiology and PneumologyUniversity Hospital HeidelbergHeidelbergGermany

Personalised recommendations