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Itraconazole and domperidone: a placebo-controlled drug interaction study

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine the influence of itraconazole on the pharmacokinetics, and the CNS and prolactin-elevating effects of domperidone in humans.

Methods

Fifteen healthy volunteers received either itraconazole (200 mg daily) or placebo for 5 days with a double blind, randomized, cross-over design. A single oral 20-mg dose of domperidone was administered to subjects on day 5. Plasma domperidone and serum prolactin concentrations were measured. The effects of domperidone on CNS were also assessed using self-rating scales and electroencephalography.

Results

Itraconazole significantly increased domperidone AUC0-∞ (3.2-fold) and Cmax (2.7-fold) compared with placebo, but had no significant effect on the elimination half-life of domperidone. The CNS effects of domperidone assessed by self-rating of mood and electroencephalography, and the prolactin-elevating effect, were not significantly affected by itraconazole. A counterclockwise hysteresis was evident in the relationship between plasma domperidone and serum prolactin concentrations. Itraconazole shifted the hysteresis to the right. Concentration–effect modeling procedures yielded a significant linear relationship between hypothetical effect site domperidone concentrations and prolactin levels. Itraconazole reduced the slope of the linear relationship.

Conclusions

Itraconazole significantly increased plasma domperidone concentrations. The interaction is probably mainly due to a reduced first pass elimination by inhibition of CYP3A and/or MDR1. The clinical significance of the altered relationship between domperidone concentrations and prolactin levels caused by itraconazole is still to be determined.

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Acknowledgements

This study was supported in part by a grant from Japan Research Foundation for Clinical Pharmacology.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan

    Tsuneaki Yoshizato, Tsutomu Kotegawa, Hiromitsu Imai, Junko Imanaga & Kyoichi Ohashi

  2. Department of Pharmaceutical Medicine and Communication, Faculty of Medicine, Oita University, Oita, Japan

    Kimiko Tsutsumi

  3. Department of Statistics, Faculty of Medicine, Oita University, Oita, Japan

    Tetsuji Ohyama

Authors
  1. Tsuneaki Yoshizato
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  2. Tsutomu Kotegawa
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  3. Hiromitsu Imai
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  4. Kimiko Tsutsumi
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  5. Junko Imanaga
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  6. Tetsuji Ohyama
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Correspondence to Tsutomu Kotegawa.

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Yoshizato, T., Kotegawa, T., Imai, H. et al. Itraconazole and domperidone: a placebo-controlled drug interaction study. Eur J Clin Pharmacol 68, 1287–1294 (2012). https://doi.org/10.1007/s00228-012-1258-x

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  • DOI: https://doi.org/10.1007/s00228-012-1258-x

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