Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice.
Parkinsonism can be a side effect of antipsychotic drugs, and has recently been reported with peripherally acting drugs such as calcium channel blockers, antiarrhythmic agents and so on. In this study, we examined the quantitative prediction of drug-induced catalepsy by amoxapine, cinnarizine and cyclophosphamide, which have been reported to induce parkinsonism. Dose-dependent catalepsy was induced by these drugs in mice. In vivo dopamine D(1), D(2) and muscarinic acetylcholine (mACh) receptor occupancies by these drugs in the striatum were also examined. The in vitro binding affinities (K(i) values) of amoxapine and cinnarizine to dopamine D(1), D(2) and mACh receptors in rat striatal synaptic membrane were 200 and 2900 nM, 58.4 and 76.4 nM and 379 and 290 nM, respectively. Cyclophosphamide did not bind to these receptors at concentrations up to 100 microM. Twenty drugs, including those mentioned above, showed a significant correlation between the observed intensity of catalepsy and the values predicted with a pharmacodynamic model (Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T. Prediction of drug-induced catalepsy based on dopamine D(1), D(2), and muscarinic acetylcholine receptor occupancies. Drug Metab Disp 1997; 25: 675-684) based on in vivo occupancy of dopamine D(1), D(2) and mACh receptors. We conclude that occupancy of dopamine D(1) and D(2) receptors contributes to catalepsy induction by amoxapine and cinnarizine.
Nasu
R
R
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Matsuo
H
H
Takanaga
H
H
Ohtani
H
H
Sawada
Y
Y
D000657:Amoxapine / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000633:toxicity; D001712:Biperiden / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000633:toxicity; D002375:Catalepsy / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D002936:Cinnarizine / Q000378:metabolism / Q000633:toxicity*; D003342:Corpus Striatum / Q000378:metabolism; D003520:Cyclophosphamide / Q000378:metabolism / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011237:Predictive Value of Tests; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D002121:Calcium Channel Blockers; D018492:Dopamine Antagonists; D018727:Muscarinic Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D001712:Biperiden; D002936:Cinnarizine; D003520:Cyclophosphamide; D000657:Amoxapine