Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms

  • Daichi Yamaguchi
  • Yasuhiro TsujiEmail author
  • Miki Sonoda
  • Kenji Shin
  • Hiroko Kito
  • Chika Ogami
  • Hidefumi Kasai
  • Hideto To
  • Hidetoshi Kamimura
Original Research Article


Background and Objective

Lithium, which is used to treat bipolar disorder, has a narrow therapeutic blood concentration range and quickly reaches clinically toxic levels. We performed a population pharmacokinetic analysis with a lithium tubular reabsorption model including urinary pH and investigated the relationship between blood lithium concentration and tremor as a side effect.


Routine clinical data, including 389 serum concentrations, were collected from 214 patients orally administered an adjusted amount of lithium carbonate. Pharmacokinetics were described using a one-compartment distribution model with first-order absorption and elimination. The fractions of the MID (Li+ + LiCO3) and ION (2Li+ + CO32−) forms were calculated using the Henderson–Hasselbalch equation, and the influences of these fractions on clearance (CL) were evaluated. The rate of tremor development was analyzed using a logit model.


Oral apparent CL (CL/F) was explained by nonrenal CL and renal CL, and renal CL was varied by the fractions of lithium forms influenced by urinary pH. The contribution of MID to CL was slightly larger than that of ION. The rate of tremor development was estimated to be more than 30% when the trough lithium concentration was greater than 1.26 mEq L−1.


Renal function and urinary pH are important indices in lithium treatment, so the serum concentration of lithium may be predicted based on the renal function and urinary pH.


Author Contributions

DY and YT contributed to the acquisition of data, analyzed and interpreted data, participated in the study design, and drafted the manuscript. CO analyzed and interpreted data and revised the manuscript. HK, HT, and HK contributed to the conception and design of the study and the interpretation of data. MS, SK, and HK contributed to serum concentration measurements and patient data sampling. All authors approved the final version to be published.

Compliance with Ethical Standards


This study was supported by a grant from SENSHIN Medical Research Foundation and Takeda Science Foundation.

Conflict of interest

The authors (Daichi Yamaguchi, Yasuhiro Tsuji, Miki Sonoda, Kenji Shin, Hiroko Kito, Chika Ogami, Hidefumi Kasai, Hideto To, and Hidetoshi Kamimura) declare no conflict of interest. All authors have completed the Unified Competing Interest form and declare that there was no support from any organization for the submitted work, no financial relationships with any organizations that may have an interest in the submitted work in the previous 3 years, and no other relationships or activities that may have influenced the submitted work.

Ethics approval

The present study was performed in accordance with the Helsinki Declaration after approval by the ethical review board of the University of Toyama (approval number: clinical 26-39). It was then approved by Yahata Kousei Hospital, Iizuka Hospital, and Fukuma Hospital.

Informed consent

Written consent was obtained from all patients, and patient privacy and personal information were respected.


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daichi Yamaguchi
    • 1
  • Yasuhiro Tsuji
    • 1
    Email author
  • Miki Sonoda
    • 2
  • Kenji Shin
    • 3
  • Hiroko Kito
    • 4
  • Chika Ogami
    • 1
  • Hidefumi Kasai
    • 1
  • Hideto To
    • 1
  • Hidetoshi Kamimura
    • 5
  1. 1.Department of Medical Pharmaceutics, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  2. 2.Department of PharmacyYahata Kousei HospitalKitakyushuJapan
  3. 3.Department of PharmacyIizuka HospitalIizukaJapan
  4. 4.Department of PharmacyFukuma HospitalFukutsuJapan
  5. 5.Department of PharmacyFukuoka University HospitalFukuokaJapan

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