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CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels

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

Abstract

Objective and methods

A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4β-hydroxycholesterol. We studied plasma 4β-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4β-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A.

Results

In patients treated with efavirenz, the median plasma 4β-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4β-hydroxycholesterol of −9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of –5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4β-hydroxycholesterol levels (p < 0.0001).

Conclusion

Changes in plasma 4β-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4β-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

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Acknowledgements

This work was supported by grants from Swedish Research Council, Medicine (3902), EDCTP (European & Developing Countries Clinical Trial Partnership, 32030), Magnus Bergwalls stiftelse, ALF-project (560177), and Torsten and Ragnar Söderbergs Foundation.

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Authors and Affiliations

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

    F. Josephson, L. Bertilsson & Y. Böttiger

  2. Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden

    L. Flamholc

  3. Department of Infectious Diseases, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

    M. Gisslén

  4. Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway

    V. Ormaasen

  5. Division of Clinical Virology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    A. Sönnerborg

  6. Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    A. Sönnerborg

  7. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    U. Diczfalusy

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  1. F. Josephson
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Correspondence to F. Josephson.

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Josephson, F., Bertilsson, L., Böttiger, Y. et al. CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels. Eur J Clin Pharmacol 64, 775–781 (2008). https://doi.org/10.1007/s00228-008-0492-8

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  • DOI: https://doi.org/10.1007/s00228-008-0492-8

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