title: Intestinal permeability and P-glycoprotein-mediated efflux transport of ticagrelor in Caco-2 monolayer cells.
abstract: Ticagrelor is the unique reversible oral antiplatelet drug commercialized today. During this study, the intestinal permeability of ticagrelor and its potential P-glycoprotein (P-gp)-mediated active transport were assessed. To this end, bidirectional transport of ticagrelor was performed across Caco-2 (human epithelial colorectal adenocarcinoma) monolayer model in the presence and absence of potent P-gp inhibitor valspodar. Ticagrelor presented an apical-basolateral apparent permeability coefficient (Papp) of 6.0 × 10-6cm/s. On the other hand, mean efflux ratio (ER) of 2.71 was observed for ticagrelor describing a higher efflux permeability compared to the influx component. Valspodar showed a significant inhibitory effect on the efflux of ticagrelor suggesting involvement of P-gp in its oral disposition. Co-incubation of the P-gp inhibitor decreased the efflux Pappof ticagrelor from 1.60 × 10-5to 1.13 × 10-5cm/s and decreased its ER by 70%. Results suggest a modest active transport of ticagrelor by P-gp across the Caco-2 cell monolayer. The co-administration of ticagrelor with a P-gp inhibitor seems altogether unlikely to have an extended impact on pharmacokinetics of ticagrelor and cause bleeding events in patients.
authors.affiliation: Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.|School of pharmaceutical sciences, Geneva University, Rue Michel Servet 1, 1211, Geneva, Switzerland.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Marsousi
authors.affiliation: Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Doffey-Lazeyras
authors.affiliation: School of pharmaceutical sciences, Geneva University, Rue Michel Servet 1, 1211, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), Missionsstrasse 64, 4055, Basel, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Rudaz
authors.affiliation: Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.|School of pharmaceutical sciences, Geneva University, Rue Michel Servet 1, 1211, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), Missionsstrasse 64, 4055, Basel, Switzerland.
authors.forename: Jules A
authors.initials: JA
authors.lastname: Desmeules
authors.affiliation: Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland.|School of pharmaceutical sciences, Geneva University, Rue Michel Servet 1, 1211, Geneva, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), Missionsstrasse 64, 4055, Basel, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001693:Biological Transport, Active / Q000502:physiology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D010539:Permeability; D021381:Protein Transport / Q000502:physiology; D000077486:Ticagrelor
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D000077486:Ticagrelor; D000241:Adenosine; C070272:valspodar
keywords: Caco-2 cell; P-glycoprotein; absorption; intestinal permeability; ticagrelor; transport