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

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.

2017

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. © 2016 Elsevier Ltd

Life
MSB - Microbiology and Systems Biology
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
CYP3A4
Ex vivo
Interplay
P-glycoprotein
Precision-cut intestinal slice
Selective P-gp inhibitor

http://resolver.tudelft.nl/uuid:1605cb45-53b9-45df-b0fe-3270559991e7

https://doi.org/10.1016/j.tiv.2016.12.002

575681

0887-2333

Toxicology in Vitro, 40, 26-33

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