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Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans

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

Abstract

Objective

To investigate the likelihood of artemisinin and thiabendazole causing pharmacokinetic interactions involving cytochrome P450 (CYP1A2) in humans given their potent inhibitory effects on the isoform in vitro.

Methods

Ten healthy volunteers received caffeine (136.5 mg), and after a washout period of 48 h, the volunteers were given a caffeine tablet (136.5 mg) together with thiabendazole (500 mg). After an additional 14 days, the volunteers received caffeine together with artemisinin (500 mg). After each treatment, plasma was obtained up to 24 h post-dose. The plasma concentrations of the drugs were measured by HPLC with UV and MS detection.

Results

Using the ratio of paraxanthine to caffeine after 4 h as an indicator of CYP1A2 activity, thiabendazole and artemisinin inhibited 92 and 66%, respectively, of the enzyme activity in vivo. In addition, the pharmacokinetics of caffeine were altered in the presence of the drugs; increases in AUC0–24 of 1.6-fold (P<0.01) and 1.3-fold of caffeine in the presence of thiabendazole and artemisinin respectively were measured. The use of in vitro data to predict the effects of thiabendazole on the formation of paraxanthine yielded good results and underestimated the effects of artemisinin when total plasma concentrations were used. Corrections for protein binding resulted in underestimation of inhibitory effects on CYP1A2.

Conclusions

Co-administration of thiabendazole or artemisinin with CYP1A2 substrates could result in clinically significant effects. Our results highlight the validity of in vitro data in predicting in vivo CYP inhibition. The formation of paraxanthine seems to be a better indicator of in vivo CYP1A2 activity than caffeine levels.

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Acknowledgements

Financial support from the African Institute of Biomedical Science and Technology (AIBST) Research Fund, AstraZeneca PLC, the International Programme in the Chemical Sciences (IPICS), Uppsala, Sweden, and the Southern African Regional Cooperation in Biochemistry, Molecular Biology and Biotechnology (SARBIO) is gratefully acknowledged. Dr Xueqing Li is also gratefully acknowledged for her assistance with LC/MS analysis of samples.

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Authors and Affiliations

  1. African Institute of Biomedical Science & Technology (AIBST), P.O. Box 2294, Harare, Zimbabwe

    Tashinga E. Bapiro & Collen M. Masimirembwa

  2. Department of Clinical Pharmacology, Muhimbili College of Health Sciences, Dar es Salaam, Tanzania

    Jane Sayi, Mary Jande, Gerald Rimoy & Amos Masselle

  3. UNESCO, Paris, France

    Julia A. Hasler

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  1. Tashinga E. Bapiro
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  2. Jane Sayi
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  7. Collen M. Masimirembwa
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Correspondence to Collen M. Masimirembwa.

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Bapiro, T.E., Sayi, J., Hasler, J.A. et al. Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans. Eur J Clin Pharmacol 61, 755–761 (2005). https://doi.org/10.1007/s00228-005-0037-3

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  • DOI: https://doi.org/10.1007/s00228-005-0037-3

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