Cabergoline

Cabergoline is a dopaminergic ergoline derivative endowed with a potent and long-lasting PRL-lowering activity. It acts by direct stimulation of the D₂-dopamine receptors on pituitary lactotrophs, thus inhibiting PRL secretion. In rats the compound decreases PRL secretion at oral doses of 3-25 mcg/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 PRL levels.

The long lasting PRL-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 single oral dose in rats (t½ of approximately 60 hours).

The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, puerperal women and hyperprolactinaemic patients. After a single oral administration of cabergoline (0.3-1.5 mg), a significant decrease in serum PRL levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7-28 days in healthy volunteers and hyperprolactinaemic patients, and up to 14-21 days in puerperal women). The PRL-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 antiprolactinaemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a very 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 only relate to blood pressure decrease. The maximal hypotensive effect of cabergoline as single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.

The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes and in female hyperprolactinaemic patients.

After oral administration of the labelled 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 was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.

In urine, the main metabolite identified was 6-allyl-8β-carboxy-ergoline, which accounted for 4-6% 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. Cabergoline biotransformation was also studied in plasma of healthy male volunteers treated with [¹⁴C]-cabergoline: a rapid and extensive biotransformation of cabergoline was shown.

The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non-radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers (using a radio-immuno assay), 79-115 hours in hyperprolactinaemic patients (using a HPLC method).

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 regimen (101 ± 43 pg/ml).

In vitro experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins. Food does not appear to affect absorption and disposition of cabergoline.

There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.

A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofoetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofoetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).