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 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 antiparkinsonianeffect 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 D 2 ) were quantitated by HPLC and with an in vivo back-titration method using [ 3 H]-raclopride, respectively. Bromocriptine induced contralateral rotations (E r o t ) 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 D 2 of bromocriptine increased gradually for 180 min after administration. The relationship between Cp and E r o t exhibited an anticlockwise hysteresis, whereas the relationship between Φ D 2 and E r o t showed a linear correlation. These results suggest that in vivo Φ D 2 is a good pharmacological indicator of the effect of a D 2 agonist. Synapse 50:110-116, 2003.