HMG-CoA reductase inhibitors and P-glycoprotein modulation

Authors

  • Katrijn Bogman,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Basel, Switzerland
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  • Anne-Kathrin Peyer,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Basel, Switzerland
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  • Michael Török,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Basel, Switzerland
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  • Ernst Küsters,

    1. Department of Chemical and Analytical Development, Novartis Pharma AG, Basel, Switzerland
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  • Jürgen Drewe

    Corresponding author
    1. Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Basel, Switzerland
      Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Petersgraben 4, CH 4031 Basel, Switzerland; E-mail: Juergen.Drewe@unibas.ch
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Department of Clinical Pharmacology and Toxicology, University Hospital/Kantonsspital, Petersgraben 4, CH 4031 Basel, Switzerland; E-mail: Juergen.Drewe@unibas.ch

Abstract

  • Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein 1a/b (mdr1a/1b).

  • P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively.

  • Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods.

  • In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.

British Journal of Pharmacology (2001) 132, 1183–1192; doi:10.1038/sj.bjp.0703920

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