METABOLITE INVOLVEMENT IN BROMOCRIPTINE-INDUCED PROLACTIN INHIBITION IN RATS

Bromocriptine (BCT) is a dopamine D2 receptor agonist used for the tre atment of Parkinson's disease and hyperprolactinemic disorders. After oral administration, BCT is metabolized into mono-or dihydroxylated me tabolites. To study how these metabolites influence parent drug pharma codynamics, we administered BCT to rats intravenously (1 mg/kg i.v.) a nd orally (10 mg/kg p.o.) and measured the inhibition of prolactin sec retion. Despite similar areas under the curve for BCT, the duration of the effect was 36 h after oral and only 18 h after intravenous admini stration. Pharmacokinetic/pharmacodynamic models were used to correlat e the concentration of BCT in the effect compartment with the lowering of prolactin. One of these models (effect compartment model) showed t hat the effective concentration (EC50) at the site of action was much lower after oral (0.56 nM) than after intravenous administration (3.68 nM). In contrast, the EC50 values based on BCT metabolite data were i n the same range for both administrations. These observations suggeste d the activity of one or more BCT metabolites. To confirm this hypothe sis, hydroxylated metabolites of BCT (produced in vitro by rat liver m icrosomes) were administered i.v. (100 mu g/kg) in rats. We found that monohydroxylated BCT was able to lower prolactin secretion like BCT. Dihydroxylated metabolites, as well as monohydroxylated metabolites, w ere effective in reducing in vitro prolactin secretion, Because we dem onstrated that the concentration of hydroxylated metabolites after ora l administration is 55-fold that of BCT, it can be concluded that BCT activity in the pituitary after oral administration is mediated by its metabolites.