title: 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.
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.
authors.affiliation: Pharmacokinetics, Toxicology & Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: liming@hec.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Pharmacokinetics, Toxicology & Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: i.a.m.de.graaf@rug.nl.
authors.forename: Inge A M
authors.initials: IA
authors.lastname: de Graaf
authors.affiliation: TNO (Netherlands Organization for Applied Scientific Research), Utrechtseweg 48, 3700 AJ Zeist, The Netherlands. Electronic address: evita.vandesteeg@tno.nl.
authors.forename: Evita
authors.initials: E
authors.lastname: van de Steeg
authors.affiliation: Pharmacokinetics, Toxicology & Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: M.H.de.Jager@rug.nl.
authors.forename: Marina H
authors.initials: MH
authors.lastname: de Jager
authors.affiliation: Pharmacokinetics, Toxicology & Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: G.M.M.Groothuis@rug.nl.
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007583:Jejunum / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000494:pharmacology; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D065692:Cytochrome P-450 CYP3A Inhibitors; D007546:Isoquinolines; D011799:Quinazolines; C013569:3-hydroxyquinidine; C087168:CP 100356; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; C070272:valspodar; D007654:Ketoconazole
keywords: CYP3A4; Ex vivo; Interplay; P-glycoprotein; Precision-cut intestinal slice; Selective P-gp inhibitor