Abstract
The distribution of domperidone (DOM), a peripheral dopamine D2 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 D2 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. D1, D2 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 D1, D2 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 D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.
| Original language | English |
|---|---|
| Pages (from-to) | 105-114 |
| Number of pages | 10 |
| Journal | Biopharmaceutics and Drug Disposition |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2003 Apr |
| Externally published | Yes |
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Keywords
- Catalepsy
- Cyclosporin A
- Domperidone
- Dopamine receptor
- Receptor occupancies
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A. / Tsujikawa, Kenji; Dan, Yukihiko; Nogawa, Kiyoko; Sato, Hitoshi; Yamada, Yasuhiko; Murakami, Hideyasu; Ohtani, Hisakazu; Sawada, Yasufumi; Iga, Tatsuji.
In: Biopharmaceutics and Drug Disposition, Vol. 24, No. 3, 04.2003, p. 105-114.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A
AU - Tsujikawa, Kenji
AU - Dan, Yukihiko
AU - Nogawa, Kiyoko
AU - Sato, Hitoshi
AU - Yamada, Yasuhiko
AU - Murakami, Hideyasu
AU - Ohtani, Hisakazu
AU - Sawada, Yasufumi
AU - Iga, Tatsuji
PY - 2003/4
Y1 - 2003/4
N2 - The distribution of domperidone (DOM), a peripheral dopamine D2 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 D2 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. D1, D2 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 D1, D2 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 D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.
AB - The distribution of domperidone (DOM), a peripheral dopamine D2 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 D2 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. D1, D2 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 D1, D2 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 D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.
KW - Catalepsy
KW - Cyclosporin A
KW - Domperidone
KW - Dopamine receptor
KW - Receptor occupancies
UR - http://www.scopus.com/inward/record.url?scp=0038753950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038753950&partnerID=8YFLogxK
U2 - 10.1002/bdd.343
DO - 10.1002/bdd.343
M3 - Article
C2 - 12673668
AN - SCOPUS:0038753950
VL - 24
SP - 105
EP - 114
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
SN - 0142-2782
IS - 3
ER -