Dostinex® Pr
Paladin
Cabergoline
Dopamine Receptor Agonist
Pharmacology
Pharmacodynamic Properties: Cabergoline, the active ingredient in Dostinex, is a dopaminergic ergoline derivative endowed with a potent and long-lasting prolactin-lowering activity. It acts by direct stimulation of the D2-dopamine receptors on pituitary lactotrophs, thus inhibiting prolactin secretion. In rats the compound decreases prolactin secretion at oral doses of 3 to 25 µg/kg, and in vitro at a concentration of 45 pg/mL. In addition, cabergoline exerts a central dopaminergic effect via D2 receptor stimulation at oral doses higher than those effective in lowering serum prolactin levels.
The long-lasting prolactin-lowering effect of cabergoline is probably due to its long persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after a single oral dose in rats (t1/2 of approximately 60 hours).
The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, puerperal women and hyperprolactinemic patients. After a single oral administration of cabergoline (0.3 to 1.5 mg), a significant decrease in serum prolactin levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7 to 28 days in healthy volunteers and hyperprolactinemic patients, and up to 14 to 21 days in puerperal women). The prolactin lowering effect is dose-related both in terms of degree of effect and duration of action.
With regard to the endocrine effects of cabergoline not related to the antiprolactinemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.
Pharmacokinetics: The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both coïtuses and in female hyperprolactinemic patients. After oral administration of the labeled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration, about 18% and 72% of the radioactive dose of 14C cabergoline was recovered in the urine and feces, respectively. Unchanged drug in urine accounted for 2 to 3% of the dose.
In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4 to 6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline in inhibiting prolactin secretion in vitro.
The low urinary excretion of unchanged cabergoline has been confirmed also in studies with nonradioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63 to 68 hours in healthy volunteers and 79 to 115 hours in hyperprolactinemic patients as assessed by radioimmunoassay).
The pharmacokinetics of cabergoline were found to be dose-independent in healthy volunteers at doses of 0.5 to 1.5 mg. On the basis of the elimination half-life, steady-state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37±8 pg/mL) and after a 4-week multiple-dose regimen (101±43 pg/mL). In vitro experiments showed that the drug at concentrations of 0.1 to 10 ng/mL is 41 to 42% bound to plasma proteins.
Food does not appear to affect absorption and disposition of cabergoline.
While renal insufficiency has been shown not to modify cabergoline kinetics, hepatic insufficiency of severe degree (>10 Child Pugh score, maximum score 12) has been shown to be associated with an increase of area under the concentration curve.
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