Journal of Anesthesia

, Volume 32, Issue 5, pp 688–693 | Cite as

In vitro changes in the proportion of protein-unbound-free propofol induced by valproate

  • Minako Ishii-Maruhama
  • Hitoshi HiguchiEmail author
  • Mai Nakanou
  • Yuka Honda-Wakasugi
  • Akiko Yabuki-Kawase
  • Shigeru Maeda
  • Takuya Miyawaki
Original Article



It has been reported that oral valproate (VPA) reduces the dose of propofol required for sedation. As  a potential reason for this, it is considered that VPA displaces serum protein-bound propofol and increases the proportion of protein-unbound-free propofol. To examine this hypothesis, the present in vitro study investigated the influence of VPA on the proportion of protein-unbound-free propofol in human serum samples.


Serum samples were collected from 10 healthy volunteers, who were not taking any medication. VPA (final concentration: 0.05, 0.1 or 1 mg/mL) and propofol (final concentration: 1 or 5 µg/mL) were mixed with serum samples with normal (4.0 g/dL) or low (2.5 g/dL) albumin concentrations. Then, protein-unbound-free propofol was extracted from the samples, and its concentration was measured using high-performance liquid chromatography. We compared the proportion of protein-unbound-free propofol in each of the VPA-containing samples with that in serum samples without VPA (control).


In the serum samples with normal albumin concentrations, 1 mg/mL VPA significantly increased the proportion of protein-unbound-free propofol at 1 and 5 µg/mL propofol. Furthermore, in the serum samples with low albumin concentrations, the proportion of protein-unbound-free propofol was significantly increased by both 0.1 and 1 mg/mL VPA at propofol concentrations of 1 and 5 µg/mL.


VPA might increase the proportion of protein-unbound-free propofol in human serum via displacement reactions.


Antiepileptic drugs Propofol Drug interactions Serum protein 



The present study was supported by institutional funding of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and a Grant-in-Aid for Young Scientists (B) (24792214) from the Japan Society for Promotion of Science.


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Copyright information

© Japanese Society of Anesthesiologists 2018

Authors and Affiliations

  1. 1.Department of Dental Anesthesiology and Special Care DentistryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  2. 2.Department of Dental AnesthesiologyOkayama University HospitalOkayamaJapan
  3. 3.Department of Anesthesiology and ICMKawasaki Medical SchoolKurashikiJapan

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