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Potentiation of domperidone‐induced catalepsy by a P‐glycoprotein inhibitor, cyclosporin A
Author(s) -
Tsujikawa Kenji,
Dan Yukihiko,
Nogawa Kiyoko,
Sato Hitoshi,
Yamada Yasuhiko,
Murakami Hideyasu,
Ohtani Hisakazu,
Sawada Yasufumi,
Iga Tatsuji
Publication year - 2003
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.343
Subject(s) - catalepsy , domperidone , pharmacology , chemistry , antagonist , in vivo , medicine , endocrinology , receptor antagonist , dopaminergic , dopamine , receptor , biology , haloperidol , microbiology and biotechnology
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. Copyright © 2003 John Wiley & Sons, Ltd.