Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A.
The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.
Tsujikawa
Kenji
K
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Japan.
Dan
Yukihiko
Y
Nogawa
Kiyoko
K
Sato
Hitoshi
H
Yamada
Yasuhiko
Y
Murakami
Hideyasu
H
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
Iga
Tatsuji
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced* / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000633:toxicity; D004294:Domperidone / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051379:Mice; D011485:Protein Binding; D011954:Receptors, Dopamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D004294:Domperidone; D016572:Cyclosporine