title: Sirolimus and everolimus intestinal absorption and interaction with calcineurin inhibitors: a differential effect between cyclosporine and tacrolimus.
abstract: The mTOR inhibitors (ImTORs) sirolimus (SRL) and everolimus (EVR) have been increasingly used in renal transplantation as part of calcineurin inhibitor (CNI) sparing or avoidance regimens. Those drugs have low and variable oral bioavailability that is increased when combined with cyclosporine or tacrolimus (TAC). We investigated the mechanisms involved in ImTORs intestinal absorption in vitro and associated it with their drug-drug interactions with CNIs. The transport of ImTORs across Caco-2 cells was studied in the apical (A) to basolateral (B) and B to A directions, in the absence or presence of cyclosporine, TAC, and GF120918 (P-gp inhibitor). In Caco-2 cells, EVR and SRL displayed a polarized transport with 8.7- and 5.9-fold higher P(app,B→A) than P(app,A→B), respectively. P-gp inhibition by GF120918 resulted in a 70 and 41% decrease in EVR and SRL efflux, respectively. Cyclosporine and TAC led to a comparable and significant decrease in the efflux ratio of ImTORs, suggesting inhibition of a P-gp-mediated efflux transport. Cyclosporine also exhibited a specific increase of P(app,B→A), which may be attributed to the inhibition of other transporters and/or metabolizing enzymes. In conclusion, EVR and SRL are both subject to an apically directed efflux mediated by P-gp. TAC mainly inhibits this efflux mechanism, while the effect of cyclosporine appears to be more complex with mechanisms to be confirmed by further studies.
authors.affiliation: INSERM UMR-S850, 2 rue du Dr marcland, 87025 Limoges, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Belkacem
authors.initials: B
authors.lastname: Boussera
authors.forename: François-Ludovic
authors.initials: FL
authors.lastname: Sauvage
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D000068338:Everolimus; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus