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The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo

Li, M., de Graaf, I. A. M., van de Steeg, E., de Jager, M. H. & Groothuis, G. M. M., Apr-2017, In : Toxicology in Vitro. 40, p. 26-33 8 p.

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  • The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo

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DOI

Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites.

Original languageEnglish
Pages (from-to)26-33
Number of pages8
JournalToxicology in Vitro
Volume40
Publication statusPublished - Apr-2017

    Keywords

  • P-glycoprotein, CYP3A4, Interplay, Selective P-gp inhibitor, Precision-cut intestinal slice, Ex vivo, PRECISION-CUT SLICES, IN-VITRO, CYTOCHROME-P450 3A, ORAL ATORVASTATIN, ENTIRE LENGTH, FEMALE RATS, GLYCOPROTEIN, METABOLISM, EXPRESSION, PROTEIN

ID: 38122118