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Research ArticleArticle

Cytochrome P450 Inhibitory Properties of Common Efflux Transporter Inhibitors

Gunilla Englund, Patrik Lundquist, Cristine Skogastierna, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius, Tommy B. Andersson and Denis Projean
Drug Metabolism and Disposition March 2014, 42 (3) 441-447; DOI: https://doi.org/10.1124/dmd.113.054932
Gunilla Englund
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Patrik Lundquist
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Cristine Skogastierna
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Jenny Johansson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Janet Hoogstraate
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Lovisa Afzelius
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Tommy B. Andersson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Denis Projean
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (G.E., P.L., C.S., J.J., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A., D.P.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
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Abstract

Drug transporter inhibitors are important tools to elucidate the contribution of transporters to drug disposition both in vitro and in vivo. These inhibitors are often unselective and affect several transporters as well as drug metabolizing enzymes, which can make experimental results difficult to interpret with confidence. We therefore tested 14 commonly used P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug-resistance associated protein (MRP) inhibitors as inhibitors of cytochrome P450 (P450) enzyme activities using recombinant enzymes. A subset of P-gp and/or CYP3A inhibitors were selected (cyclosporin A, elacridar, ketoconazole, quinidine, reserpine, and tacrolimus) for a comparison of P450 inhibition in human microsomes and hepatocytes. Most P-gp inhibitors showed CYP3A4 inhibition, with potencies often in a similar range as their P-gp inhibition, as well as less potent CYP2C19 inhibition. Other P450 enzymes were not strongly inhibited except a few cases of CYP2D6 inhibition. MRP and BCRP inhibitors showed limited P450 inhibition. Some inhibitors showed less P450 inhibition in human hepatocytes than human liver microsomes, for example, elacridar, probably due to differences in binding, permeability limitations, or active, P-gp mediated efflux of the inhibitor from the hepatocytes. Quinidine was a potent P450 inhibitor in hepatocytes but only showed weak inhibition in microsomes. Quinidine shows an extensive cellular uptake, which may potentiate intracellular P450 inhibition. Elacridar, described as a potent and selective P-gp inhibitor, displayed modest P450 inhibition in this study and is thus a useful model inhibitor to define the role of P-gp in drug disposition without interference with other processes.

Footnotes

    • Received September 17, 2013.
    • Accepted January 6, 2014.
  • G.E. and P.L. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.113.054932.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

P450 Inhibition by Efflux Transporter Inhibitors

Gunilla Englund, Patrik Lundquist, Cristine Skogastierna, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius, Tommy B. Andersson and Denis Projean
Drug Metabolism and Disposition March 1, 2014, 42 (3) 441-447; DOI: https://doi.org/10.1124/dmd.113.054932

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Research ArticleArticle

P450 Inhibition by Efflux Transporter Inhibitors

Gunilla Englund, Patrik Lundquist, Cristine Skogastierna, Jenny Johansson, Janet Hoogstraate, Lovisa Afzelius, Tommy B. Andersson and Denis Projean
Drug Metabolism and Disposition March 1, 2014, 42 (3) 441-447; DOI: https://doi.org/10.1124/dmd.113.054932
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