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Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo

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

Abstract

Objective

To study the extent of in vivo inhibition by the antimalarial drug amodiaquine, its active metabolite N-desethylamodiaquine, or both, of the metabolism of four probe drugs of the enzymes CYP2D6, CYP2C19, CYP2C9 and CYP1A2.

Methods

Twelve healthy Swedish volunteers received a cocktail of four probe drugs (debrisoquine, omeprazole, losartan and caffeine) to determine their baseline metabolic capacities. After a washout period, they received a 600 mg oral dose of amodiaquine hydrochloride; and 2–3 h later the cocktail was administered again. One week after the intake of amodiaquine, the subjects received the cocktail a third time. The levels of probe drugs and their metabolites as well as amodiaquine and its metabolite were determined by HPLC.

Results

Plasma levels of amodiaquine and N-desethylamodiaquine could be followed in all subjects for 6 h and 28 days, respectively. Among the 12 subjects, a 3-fold variation in amodiaquine AUC and a 2-fold variation in N-desethylamodiaquine AUC, were observed. The CYP2D6 and CYP2C9 activities of the subjects were measured by debrisoquine and losartan phenotyping tests, respectively. There were significant mean increases in debrisoquine metabolic ratio (MR) between baseline and the second cocktail [MR2 h−MRbaseline 1.426 (95% confidence interval 1.159, 1.755), P=0.002; ANOVA, Fisher LSD test] and in mean losartan MR between baseline and the second cocktail [MR2 h−MRbaseline 1.724 (95% confidence interval 1.076, 2.762), P=0.026; ANOVA, Fisher LSD test]. The effects on CYP2D6 and CYP2C9 activities subsided within a week after intake of amodiaquine as tested by the phenotyping cocktail. The changes in omeprazole MRs and caffeine MRs were not statistically significant between any of the study phases.

Conclusion

A single dose of amodiaquine decreased CYP2D6 and CYP2C9 activities significantly compared to baseline values. Amodiaquine has the potential to cause drug-drug interactions and should be further investigated in malarial patients treated with drug combinations containing amodiaquine.

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Acknowledgements

We gratefully acknowledge the work done by the research nurse Susann Schrey, Magnus Christensen, MD, and technician Lilleba Bohman for genotyping assays, as well as MSc Mia Sandberg, MSc Tommy Pettersson, MSc Annika Allqvist and technician Ulla Petterson for assistance with analytical assays. This work was supported by the Swedish Medical Research Council (3902), National Institutes of Health, USA (grant R01 GM60548-3), the Swedish Agency for Research Collaboration with Developing Countries (SAREC) at the Swedish International Development Cooperation Agency (SIDA) (SWE-1999-260, 99-266 Bil. Th. 106, SWE-2000-175 and SWE-2002-063), Karolinska Institute (postgraduate studentship) and the Swedish Society for Medical Research (research grants for PhD student No. A200100225 and A200300875).

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Authors and Affiliations

  1. Division of Clinical Pharmacology C1:68, Karolinska University Hospital - Huddinge, SE-141 86, Stockholm, Sweden

    Agneta Wennerholm, Maria Pihlsgård, Margarita Mahindi, Leif Bertilsson & Lars L. Gustafsson

  2. Bioanalysis Södertälje, Global Development DMPK, Astra Zeneca R&D, Södertälje, Sweden

    Anna Nordmark

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  1. Agneta Wennerholm
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Correspondence to Lars L. Gustafsson.

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Wennerholm, A., Nordmark, A., Pihlsgård, M. et al. Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo. Eur J Clin Pharmacol 62, 539–546 (2006). https://doi.org/10.1007/s00228-006-0121-3

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