PT  - JOURNAL ARTICLE
AU  - Valente, Delphine
AU  - Delaforge, Marcel
AU  - Urien, Saik
AU  - Guivarc’H, Dominique
AU  - Vienet, Raymond
AU  - Grognet, Jean-Marc
AU  - Ezan, Eric
TI  - Metabolite Involvement in Bromocriptine-Induced Prolactin Inhibition in Rats
DP  - 1997 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1418--1424
VI  - 282
IP  - 3
4099  - http://jpet.aspetjournals.org/content/282/3/1418.short
4100  - http://jpet.aspetjournals.org/content/282/3/1418.full
SO  - J Pharmacol Exp Ther1997 Sep 01; 282
AB  - 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 (producedin vitro by rat liver microsomes) were administered i.v. (100 μg/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. The American Society for Pharmacology and Experimental Therapeutics