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Rapid CommunicationShort Communication

Atorvastatin Treatment Induces Uptake and Efflux Transporters in Human Liver

Linda Björkhem-Bergman, Helena Bergström, Maria Johansson, Paolo Parini, Mats Eriksson, Anders Rane and Lena Ekström
Drug Metabolism and Disposition September 2013, 41 (9) 1610-1615; DOI: https://doi.org/10.1124/dmd.113.051698
Linda Björkhem-Bergman
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Helena Bergström
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Maria Johansson
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Paolo Parini
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Mats Eriksson
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Anders Rane
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Lena Ekström
Division of Clinical Pharmacology (L.B.-B., H.B., M.J., A.R., L.E.), Division of Clinical Chemistry (P.P.), and Departments of Laboratory Medicine and Medicine, Division of Endocrinology (M.E.), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Abstract

The metabolism and disposition of statins are highly dependent on different cytochrome P450 enzymes, such as CYP3A4 and CYP2C9, as well as membrane transporters SLCO1B1, SLCO2B1, ABCB1, and ABCG2. Interindividual gene expression differences among these enzymes may explain part of the variability in tolerance and effect for statin treatment. The aim of the present study was to investigate the effect of statin treatment on these genes in human liver tissue. Levels of CYP3A4, CYP2C9, SLCO1B1, SLCO2B1, ABCB1, and ABCG2 mRNA in liver tissue from a previously performed clinical trial in 29 patients randomized to treatment with placebo, 80 mg/day of atorvastatin, or 20 mg/day of fluvastatin for 4 weeks were measured using quantitative polymerase chain reaction. Treatment with atorvastatin (n = 10), but not with fluvastatin (n = 10), resulted in 3-fold higher expression of SLCO2B1 compared with placebo-treated patients (n = 9) (P < 0.05). Atorvastatin increased the expression of both ABCB1 and ABCG2 by more than 2-fold (P < 0.05). No difference was found in CYP2C9, CYP3A4, or SLCO1B1 mRNA expression in patients administered statins or those administered placebo. Premenopausal women (n = 8) had higher expression of CYP3A4 (P < 0.05) and lower expression of CYP2C9 (P < 0.05) compared with postmenopausal women (n = 10) and men (n = 11), respectively. Here we show for the first time that atorvastatin treatment leads to increased expression of the membrane transporters SLCO2B1, ABCB1, and ABCG2 in human liver tissue, which potentially may counteract the efficacy of the treatment, and our findings may cast light on the mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment.

Footnotes

    • Received February 21, 2013.
    • Accepted June 10, 2013.
  • Financial support was provided through the regional agreement on training and clinical research (ALF) between Karolinska Institutet and Stockholm County Council; the Swedish Foundation for Clinical Pharmacology and Pharmacotherapy; grants from Pfizer (unrestricted); Swedish Heart and Lung Foundation; Magnus Bergwall Stiftelse; Karolinska Institutet; and the Swedish Science Council (Grant 04496 AR).

  • dx.doi.org/10.1124/dmd.113.051698.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (9)
Drug Metabolism and Disposition
Vol. 41, Issue 9
1 Sep 2013
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Rapid CommunicationShort Communication

Atorvastatin Induces Expression of Membrane Transporters

Linda Björkhem-Bergman, Helena Bergström, Maria Johansson, Paolo Parini, Mats Eriksson, Anders Rane and Lena Ekström
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1610-1615; DOI: https://doi.org/10.1124/dmd.113.051698

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Rapid CommunicationShort Communication

Atorvastatin Induces Expression of Membrane Transporters

Linda Björkhem-Bergman, Helena Bergström, Maria Johansson, Paolo Parini, Mats Eriksson, Anders Rane and Lena Ekström
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1610-1615; DOI: https://doi.org/10.1124/dmd.113.051698
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