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Pharmacokinetic and pharmacodynamic analyses, based on dopamine D 2 ‐receptor occupancy of bromocriptine, of bromocriptine‐induced contralateral rotations in unilaterally 6‐OHDA‐lesioned rats
Author(s) -
Atsumi Masako,
Kawakami Junichi,
Sugiyama Erika,
Kotaki Hajime,
Sawada Yasufumi,
Sato Hitoshi,
Yamada Yasuhiko,
Iga Tatsuji
Publication year - 2003
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10248
Subject(s) - bromocriptine , agonist , medial forebrain bundle , dopamine receptor d2 , pharmacology , raclopride , chemistry , dopamine , dopamine agonist , in vivo , endocrinology , medicine , dopamine receptor , receptor , striatum , biology , prolactin , hormone , microbiology and biotechnology
Bromocriptine is a selective agonist for dopamine D 2 ‐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 D 2 ‐receptor occupancy (Φ 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 Φ 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 Φ D2 and E rot showed a linear correlation. These results suggest that in vivo Φ D2 is a good pharmacological indicator of the effect of a D 2 agonist. Synapse 50:110–116, 2003. © 2003 Wiley‐Liss, Inc.