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Metabolism and elimination of quinine in healthy volunteers

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

Abstract

Objectives

The aims were to investigate: (1) The renal elimination of quinine and its metabolites 3-hydoxyquinine, 2′-quininone, (10R) and (10S)-11-dihydroxydihydroquinine and (2) the relative importance of CYP3A4, CYP1A2 and CYP2C19 for the formation of 2′-quininone, (10R) and (10S)-11-dihydroxydihydroquinine in vivo.

Methods

In a randomised three-way crossover study, nine healthy Swedish subjects received a single oral dose of quinine hydrochloride (500 mg), on three different occasions: (A) alone, (B) concomitantly with ketoconazole (100 mg twice daily for 3 days) and (C) concomitantly with fluvoxamine (25 mg twice daily for 2 days). Blood and urine samples were collected before quinine intake and up to 96 h thereafter. All samples were analysed by means of high-performance liquid chromatography.

Results

Co-administration with ketoconazole significantly increased the area under the plasma concentration versus time curve (AUC) of 2′-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine, the geometric mean ratios (90% CI) of the AUC were 1.9 (1.8, 2.0), 1.3 (1.1, 1.7) and 1.6 (1.4, 1.8), respectively. Co-administration with fluvoxamine had no significant effect on the mean AUC of any of the metabolites. A mean of 56% of the administered oral quinine dose was recovered in urine after hydrolysis with β-glucuronidase relative to the 40% recovered before hydrolysis.

Conclusion

Quinine is eliminated in urine mainly as unchanged drug and as 3-hydroxyquinine. The major metabolite of quinine is 3-hydroxyquinine formed by CYP3A4. There is no evidence for the involvement of CYP3A4, 1A2 or 2C19 in the formation of 2′-quininone, (10S)-11-dihydroxydihydroquinine and (10R)-11-dihydroxydihydroquinine in vivo. Glucuronidation is an important pathway for the renal elimination of quinine, mainly as direct conjugation of the drug.

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Acknowledgements

This work was supported by the Swedish Agency for Research Collaboration with Developing Countries grants no. Bil Tz 16/98 75007059, SWE 1997–221, 1998–394, 1999–260, 2000–175, the Swedish Medical Research Council grant no. 3902, the National Institutes of Health, USA (1R01 GM60548–02) and funds from Karolinska Institutet. We extend our thanks to the research nurses Katarina Andersson and Eva Götharson for their professional help in performing the study.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Laboratory Medicine and Technology, C1–68, Huddinge University Hospital, 141 86 , Stockholm, Sweden

    Rajaa A. Mirghani, Leif Bertilsson & Lars L. Gustafsson

  2. Division of Infectious Diseases, Karolinska Institutet at Huddinge University Hospital, 141 86 , Stockholm, Sweden

    Urban Hellgren

  3. National Board of Health and Welfare, 106 30, Stockholm, Sweden

    Örjan Ericsson

Authors
  1. Rajaa A. Mirghani
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  2. Urban Hellgren
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  3. Leif Bertilsson
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  4. Lars L. Gustafsson
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  5. Örjan Ericsson
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Corresponding author

Correspondence to Rajaa A. Mirghani.

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Mirghani, R.A., Hellgren, U., Bertilsson, L. et al. Metabolism and elimination of quinine in healthy volunteers. Eur J Clin Pharmacol 59, 423–427 (2003). https://doi.org/10.1007/s00228-003-0637-8

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  • DOI: https://doi.org/10.1007/s00228-003-0637-8

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