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. (April 2017)

• Record Type: Journal Article
• Authors: Li, Ming; de Graaf, Inge A.M.; van de Steeg, Evita; de Jager, Marina H.; Groothuis, Geny M.M.
• Is Part Of: Toxicology in vitro. Volume 40(2017)
• Page Start: 26
• Page End: 33
• Publication Date: 2017-04
• Subjects: 3OH-Qi 3-hydroxy-quinidine -- ADME-Tox absorption, distribution, metabolism, excretion and toxicity -- CP100356 N-(3, 4-dimethoxyphenethyl)-4-(6, 7-dimethoxy-3, 4-dihydroisoquinolin-2[1H]-yl)-6, 7-dimethoxyquinazolin-2-amine -- CYP cytochrome P450 -- DDI(s) drug-drug interaction(s) -- HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonic acid -- PCIS precision-cut intestinal slices -- P-gp P-glycoprotein -- PSC833 Valspodar, 6-[(2S, 4R, 6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-l-valine-cyclosporin A -- Qi quinidine; P-glycoprotein -- CYP3A4 -- Interplay -- Selective P-gp inhibitor -- Precision-cut intestinal slice -- Ex vivo; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2016.12.002
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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. Highlights: Drug-drug interactions are different in human jejunum, ileum, and colon ex vivo . Human intestinal slices are an efficient model to predict drug/drug interactions. P-gp inhibition results in increased concentrations of drugs and metabolites in the intestine.