European Journal of Clinical Pharmacology

, Volume 75, Issue 3, pp 351–361 | Cite as

Effects of magnesium oxide on pharmacokinetics of L-dopa/carbidopa and assessment of pharmacodynamic changes by a model-based simulation

  • Yushi Kashihara
  • Yui Terao
  • Kensaku Yoda
  • Takeshi Hirota
  • Toshio Kubota
  • Miyuki Kimura
  • Shunji Matsuki
  • Masaaki Hirakawa
  • Shin Irie
  • Ichiro IeiriEmail author
Pharmacokinetics and Disposition



Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson’s disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA).


The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa.


In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC0–12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa.


This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.


L-Dopa/carbidopa Magnesium oxide Interaction Pharmacokinetics Model-based meta-analysis 



The authors are grateful to the subjects who were involved in this study and the staff at the SOUSEIKAI Fukuoka Mirai Hospital Clinical Research Center. The authors thank Satoru Koyanagi and Naoya Matsunaga for animal handling assistance.

Author contributions

Y.K., Y.T., and T.H. wrote the paper. Y.K., Y.T., T.K., M.K., M.H., S.I., T.H., and I.I designed the research. Y.K., Y.T., and K.Y performed the research. Y.K. and Y.T. analyzed the data. I critically reviewed the manuscript for intellectual content.


This study was funded by the Japan Research Foundation for Clinical Pharmacology.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the Experimental Animal Care and Use Committee of Kyushu University according to the National Institutes of Health guidelines.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

228_2018_2568_MOESM1_ESM.docx (336 kb)
ESM 1 (DOCX 336 kb)


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Copyright information

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

Authors and Affiliations

  • Yushi Kashihara
    • 1
  • Yui Terao
    • 1
  • Kensaku Yoda
    • 1
    • 2
  • Takeshi Hirota
    • 1
  • Toshio Kubota
    • 3
  • Miyuki Kimura
    • 4
  • Shunji Matsuki
    • 4
  • Masaaki Hirakawa
    • 2
  • Shin Irie
    • 4
  • Ichiro Ieiri
    • 1
    Email author
  1. 1.Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical SciencesKyushu UniversityHigashi-kuJapan
  2. 2.Hospital Pharmacy, Fukuoka Tokushukai Medical CenterFukuokaJapan
  3. 3.Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
  4. 4.SOUSEIKAI Fukuoka Mirai Hospital Clinical Research CenterFukuokaJapan

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