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Research ArticleArticle

The Consequence of Drug–Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

Ming Li, Inge A. M. de Graaf, Sanna Siissalo, Marina H. de Jager, Annie van Dam and Geny M. M. Groothuis
Drug Metabolism and Disposition May 2016, 44 (5) 683-691; DOI: https://doi.org/10.1124/dmd.115.068684
Ming Li
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Inge A. M. de Graaf
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Sanna Siissalo
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Marina H. de Jager
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Annie van Dam
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Geny M. M. Groothuis
Groningen Research Institute of Pharmacy (M.L., I.A.M.G., S.S., M.H.J. G.M.M.G.), and Interfaculty Mass Spectrometry Center (A.D.), University of Groningen, Groningen, the Netherlands
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Abstract

P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) are differentially expressed along the intestine and work coordinately to reduce the intracellular concentration of xenobiotics and the absorption of orally taken drugs. Drug–drug interactions (DDIs) based on P-gp/CYP3A interplay are of clinical importance and require preclinical investigation. We investigated the P-gp/Cyp3a interplay and related DDIs with different P-gp inhibitors in the various regions of the rat intestine ex vivo using precision-cut intestinal slices (PCIS) with quinidine (Qi), a dual substrate of P-gp and Cyp3a, as the probe. The results showed that P-gp efflux was the main factor limiting the intracellular Qi content at concentrations below 5 µM, whereas both efflux and metabolism were saturated at [Qi] > 50 µM. The selective P-gp inhibitors CP100356 [N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine] and PSC833 [valspodar, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporin A] enhanced the Qi accumulation in slices in line with the different P-gp expression in the intestinal regions and, as a result, also enhanced metabolism in the jejunum and ileum. Dual inhibitors of both P-gp and Cyp3a (verapamil and ketoconazole) increased the concentration of Qi in the jejunum and ileum, but less 3-hydroxy-quinidine was produced due to inhibition of Cyp3a. The results indicate that the P-gp/Cyp3a interplay depends on the concentration of the drug and on the intestinal region under study. Furthermore, due to the P-gp/Cyp3a interplay, DDIs can lead to remarkable changes in the intracellular concentration of both the parent drug and the metabolite, which varies among the intestinal regions and depends on the selectivity of the inhibitors, with potentially important implications for disposition and toxicity of drugs and their metabolites.

Footnotes

    • Received December 1, 2015.
    • Accepted February 29, 2016.
  • ↵1 Current affiliation: Association of Finnish Pharmacies, Helsinki, Finland.

  • dx.doi.org/10.1124/dmd.115.068684.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
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Research ArticleArticle

Effect of P-gp Inhibitors on P-gp/CYP3A Interplay

Ming Li, Inge A. M. de Graaf, Sanna Siissalo, Marina H. de Jager, Annie van Dam and Geny M. M. Groothuis
Drug Metabolism and Disposition May 1, 2016, 44 (5) 683-691; DOI: https://doi.org/10.1124/dmd.115.068684

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Research ArticleArticle

Effect of P-gp Inhibitors on P-gp/CYP3A Interplay

Ming Li, Inge A. M. de Graaf, Sanna Siissalo, Marina H. de Jager, Annie van Dam and Geny M. M. Groothuis
Drug Metabolism and Disposition May 1, 2016, 44 (5) 683-691; DOI: https://doi.org/10.1124/dmd.115.068684
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