Metabolite involvement in bromocriptine-induced prolactin inhibition in rats.

Bromocriptine (BCT) is a dopamine D2 receptor agonist used for the treatment of Parkinson's disease and hyperprolactinemic disorders. After oral administration, BCT is metabolized into mono- or dihydroxylated metabolites. To study how these metabolites influence parent drug pharmacodynamics, we administered BCT to rats intravenously (1 mg/kg i.v.) and orally (10 mg/kg p.o.) and measured the inhibition of prolactin secretion. Despite similar areas under the curve for BCT, the duration of the effect was 36 h after oral and only 18 h after intravenous administration. Pharmacokinetic/pharmacodynamic models were used to correlate the concentration of BCT in the effect compartment with the lowering of prolactin. One of these models (effect compartment model) showed that 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 in the same range for both administrations. These observations suggested the activity of one or more BCT metabolites. To confirm this hypothesis, hydroxylated metabolites of BCT (produced in vitro by rat liver microsomes) were administered i.v. (100 microg/kg) in rats. We found that monohydroxylated BCT was able to lower prolactin secretion like BCT. Dihydroxylated metabolites, as well as monohydroxylated metabolites, were effective in reducing in vitro prolactin secretion. Because we demonstrated that the concentration of hydroxylated metabolites after oral 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.