title: Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp).
abstract: The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.
authors.affiliation: Department of Psychiatry, University of Mainz, Mainz, Germany. schmitt@psychiatrie.klinik.uni-mainz.de
authors.forename: U
authors.initials: U
authors.lastname: Schmitt
authors.forename: A
authors.initials: A
authors.lastname: Abou El-Ela
authors.forename: L J
authors.initials: LJ
authors.lastname: Guo
authors.forename: H
authors.initials: H
authors.lastname: Glavinas
authors.forename: P
authors.initials: P
authors.lastname: Krajcsi
authors.forename: J M
authors.initials: JM
authors.lastname: Baron
authors.forename: C
authors.initials: C
authors.lastname: Tillmann
authors.forename: C
authors.initials: C
authors.lastname: Hiemke
authors.forename: P
authors.initials: P
authors.lastname: Langguth
authors.forename: S
authors.initials: S
authors.lastname: Härtter
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D013469:Sulpiride; D000077582:Amisulpride; D016572:Cyclosporine