Skip to main content
SpringerLink
Log in

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

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

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.

Methods

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.

Results

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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2:349–52.

    CAS  PubMed  Google Scholar 

  2. Schou M. Lithium in psychiatric therapy and prophylaxis. J Psychiatr Res. 1968;6:67–95.

    Article  CAS  PubMed  Google Scholar 

  3. Grandjean EM, Aubry J-M. Lithium: updated human knowledge using an evidence-based approach. Part I: clinical efficacy in bipolar disorder. CNS Drugs. 2009;23:225–40.

  4. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672–82.

    Article  CAS  PubMed  Google Scholar 

  5. Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord. 2007;9:551–60.

    Article  CAS  PubMed  Google Scholar 

  6. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375–89.

    Article  CAS  PubMed  Google Scholar 

  7. Schou M. Pharmacology and toxicology of lithium. Annu Rev Pharmacol Toxicol. 1976;16:231–43.

    Article  CAS  PubMed  Google Scholar 

  8. Thomsen K, Olesen OV. Precipitating factors and renal mechanisms in lithium intoxication. Gen Pharmacol. 1978;9:85–9.

    Article  CAS  PubMed  Google Scholar 

  9. Thomsen K. Renal handling of lithium at non-toxic and toxic serum lithium levels. A review. Dan Med Bull. 1978;25:106–15.

    CAS  PubMed  Google Scholar 

  10. Kanba S, Kato T, Terao T, Yamada K. Guideline for treatment of bipolar disorder by the Japanese Society of Mood Disorders, 2012. Psychiatry Clin Neurosci. 2013;67:285–300.

    Article  PubMed  Google Scholar 

  11. Schou M, Amdisen A, Trap-Jensen J. Lithium poisoning. Am J Psychiatr. 1968;125:520–7.

    Article  CAS  PubMed  Google Scholar 

  12. Prien RF, Caffey EM, Klett CJ. Relationship between serum lithium level and clinical response in acute mania treated with lithium. Br J Psychiatry. 1972;120:409–14.

    Article  CAS  PubMed  Google Scholar 

  13. Gelenberg A, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321:1489–93.

    Article  CAS  PubMed  Google Scholar 

  14. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721–8.

    Article  CAS  PubMed  Google Scholar 

  15. Watanabe S. Side effects of antimanic drugs. Jpn J Neuropsychopharmacol. 1989;11:49–58.

  16. Ebid AIM, Abd-allah DAT, Elhabiby MMM. Pharmacokinetics of lithium in Egyptian bipolar patients: dosage adjustment approach. Pharmacol Pharm. 2014;5:425–32.

  17. Henderson L. Concerning the relationship between the strength of acids and their capacity to preserve neutrality. Am J Physiol. 1908;21:173–9.

    Article  CAS  Google Scholar 

  18. Hasselbalch K. Die Berechnung der Wasserstoffzahl des Blutes aus der freien und gebundenen Kohlensäure desselben, und die Sauerstoffbindung des Blutes als Funktion der Wasserstoffzahl. Biochem Z. 1917;78:112–44.

    Google Scholar 

  19. Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205–19.

    Article  PubMed  Google Scholar 

  20. Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.

    Article  CAS  PubMed  Google Scholar 

  21. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102:2941–52.

    Article  CAS  PubMed  Google Scholar 

  22. Anderson BJ, Holford NHG. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24:25–36.

    Article  CAS  PubMed  Google Scholar 

  23. Cockcroft DW, Gault H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  Google Scholar 

  24. Mould DR, et al. Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther. 2002;71:334–48.

    Article  CAS  PubMed  Google Scholar 

  25. Matthews I, Kirkpatrick C, Holford N. Quantitative justification for target concentration intervention—parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. Br J Clin Pharmacol. 2004;58:8–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Parke J, Holford NHG, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999;59:19–29.

    Article  CAS  PubMed  Google Scholar 

  27. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Thornhill DP. Pharmacokinetics of ordinary and sustained-release lithium carbonate in manic patients after acute dosage. Eur J Clin Pharmacol. 1978;14:267–71.

    Article  CAS  PubMed  Google Scholar 

  29. Turck D, Heinzel G, Luik G. Steady-state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam. Br J Clin Pharmacol. 2000;50:197–204.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Nielsen-Kudsk F, Amedisen A. Analysis of the pharmacokinetics of lithium in man. Eur J Clin Pharmacol. 1979;16:271–7.

    Article  CAS  Google Scholar 

  31. Yukawa E, Nomiyama N, Higuchi S, Aoyama T. Lithium population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens. Ther Drug Monit. 1993;15:75–82.

    Article  CAS  PubMed  Google Scholar 

  32. Wing YK, Chan E, Chan K, Lee S, Shek CC. Lithium pharmacokinetics in Chinese manic-depressive patients. J Clin Psychopharmacol. 1997;17:179–84.

  33. Findling RL, et al. First-dose pharmacokinetics of lithium carbonate in children and adolescents. J Clin Psychopharmacol. 2010;30:404–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Vesterqaard P, Poulstrup I, Schou M. Prospective studies on a lithium cohort. 3. Tremor, weight gain, diarrhea, psychological complaints. Acta Psychiatr Scand. 1988;78:434–41.

  35. Feng Y, et al. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol. 2014;78:106–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-1094, Japan

    Daichi Yamaguchi, Yasuhiro Tsuji, Chika Ogami, Hidefumi Kasai & Hideto To

  2. Department of Pharmacy, Yahata Kousei Hospital, 3-12-12 Satonaka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-0846, Japan

    Miki Sonoda

  3. Department of Pharmacy, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-8505, Japan

    Kenji Shin

  4. Department of Pharmacy, Fukuma Hospital, 1-5-1 Hanamigahama, Fukutsu, Fukuoka, 811-3295, Japan

    Hiroko Kito

  5. Department of Pharmacy, Fukuoka University Hospital, 7-45-1 Nanakuma, Zyounan-ku, Fukuoka, 814-0180, Japan

    Hidetoshi Kamimura

Authors
  1. Daichi Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhiro Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miki Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroko Kito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chika Ogami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidefumi Kasai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideto To
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hidetoshi Kamimura
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Yasuhiro Tsuji.

Ethics declarations

Funding

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamaguchi, D., Tsuji, Y., Sonoda, M. et al. Population Pharmacokinetics and Exposure–Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms. Eur J Drug Metab Pharmacokinet 44, 329–338 (2019). https://doi.org/10.1007/s13318-018-0536-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-018-0536-0

Search

Navigation