Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp).
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.
Schmitt
U
U
Department of Psychiatry, University of Mainz, Mainz, Germany. schmitt@psychiatrie.klinik.uni-mainz.de
Abou El-Ela
A
A
Guo
L J
LJ
Glavinas
H
H
Krajcsi
P
P
Baron
J M
JM
Tillmann
C
C
Hiemke
C
C
Langguth
P
P
Härtter
S
S
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D013469:Sulpiride; D000077582:Amisulpride; D016572:Cyclosporine