Pharmacokinetic and pharmacodynamic analyses, based on dopamine D2-receptor occupancy of bromocriptine, of bromocriptine-induced contralateral rotations in unilaterally 6-OHDA-lesioned rats.
Bromocriptine is a selective agonist for dopamine D2-receptors and is used in the treatment of Parkinson's disease. In this study, we performed pharmacokinetic and pharmacodynamic (PK/PD) analyses of the antiparkinsonian effect of bromocriptine and evaluated drug-induced contralateral rotations in rats in which unilateral striatal lesions had been generated by microinjection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The plasma concentration (Cp) and D2 receptor occupancy (Phi(D2)) were quantitated by HPLC and with an in vivo back-titration method using [(3)H]-raclopride, respectively. Bromocriptine induced contralateral rotations (E(rot)) in a dose-dependent manner following intraperitoneal administration in an animal model of Parkinson's disease. The Cp of bromocriptine peaked at 15-30 min after the administration and decreased time-dependently, whereas the Phi(D2) of bromocriptine increased gradually for 180 min after administration. The relationship between Cp and E(rot) exhibited an anticlockwise hysteresis, whereas the relationship between Phi(D2) and E(rot) showed a linear correlation. These results suggest that in vivo Phi(D2) is a good pharmacological indicator of the effect of a D2 agonist.
Atsumi
Masako
M
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, 113-8655, Japan.
Kawakami
Junichi
J
Sugiyama
Erika
E
Kotaki
Hajime
H
Sawada
Yasufumi
Y
Sato
Hitoshi
H
Yamada
Yasuhiko
Y
Iga
Tatsuji
T
D000818:Animals; D001971:Bromocriptine / Q000097:blood / Q000493:pharmacokinetics*; D003714:Denervation; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D012399:Rotation; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D016627:Oxidopamine