Pharmacokinetics, pharmacodynamics, and tolerability of cabergoline, a prolactin-lowering drug, after administration of increasing oral doses (0.5, 1.0, and 1.5 milligrams) in healthy male volunteers.

Abstract

Cabergoline (CAB) a long-acting dopaminergic ergoline derivative, was given orally, in single doses of 0.5, 1.0, and 1.5 mg, to 12 healthy men in order to evaluate its PRL-lowering effect as well as its plasma pharmacokinetics and urinary excretion. Drug administrations were separated by 5-week washout periods. Blood samples for PRL and CAB determination were taken at baseline and for 840 h thereafter (every 1 h up to 4 h, every 4 h up to 12 h, every 24 h up to 168 h, and weekly up to 5 weeks). Fractional urine collections for CAB excretion were taken immediately before drug administration, every 4 h up to 12 h, and every 12 h up to 168 h. During the study period, blood pressure and heart rate were monitored at the same time periods of plasma sampling for CAB, and electrocardiographic tracings and hematological evaluations were performed before and after each treatment period. All CAB doses (0.5, 1.0, and 1.5 mg) produced in all subjects a complete PRL suppression (PRL < 1.0 micrograms/L), that occurred earlier and persisted longer with the two higher doses. PRL secretion areas [area under the curve (AUC) 0-48 h and 48-840 h] were higher after 0.5-mg than after 1.0- and 1.5-mg doses. In particular, in the first portion of the area, the difference between 0.5 mg and both 1.0 and 1.5 mg was highly statistically significant (P < 0.01) without significant differences between the two highest doses. Mean CAB maximal plasma concentrations (Cmax) were 33.3 +/- 3.69, 40.3 +/- 2.49, and 67.0 +/- 9.79 ng/L after 0.5, 1.0, and 1.5 mg CAB, respectively; time to Cmax was 2 h (median) for all doses; CAB AUC(0-168 h) after 0.5 mg CAB was significantly lower (P < 0.01) than after 1.5 mg CAB. The percentages of the administered doses of CAB excreted in urine were 1.1 +/- 0.1%, 1.1 +/- 0.1%, and 1.2 +/- 0.1% for the 0.5-, 1.0-, and 1.5 mg doses, respectively (P = NS). CAB AUCs(0-168 h) and Cmax normalized to the 1.0-mg dose were compared by two-way analysis of variance; no significant differences were found for CAB AUCs(0-168h); Cmax after 0.5 mg was significantly higher (P < 0.01) than after 1.0 and 1.5 mg CAB. A progressive decrease of systolic and diastolic blood pressure was observed, and symptomatic hypotension after the 1.0-mg dose did not allow one subject to receive the 1.5-mg dose. Other mild to moderate adverse events occurred only after 1.0 and 1.5 mg CAB. These results indicate that, in the dose range of 0.5-1.5 mg, the pharmacokinetics of CAB are dose independent, and that the pharmacodynamic data and the frequencies of adverse events of CAB are dose related, with no significant differences in the PRL-lowering effect of the 1.0- and 1.5-mg doses.

Dopamine gene predicts the brain's response to dopaminergic drug

“…, 1994; Rabey et al. , 1994; Andreotti et al. , 1995; Del Dotto & Bonuccelli, 2003), so it is possible that some residual cabergoline was in the blood stream of subjects who received the drug on the first testing session.…”

“…Thus, neither the subjects nor the experimenters knew the genotype during the scanning sessions. After an approximate 90‐min delay to allow the drug to be absorbed (Andreotti et al. , 1995), subjects had the procedures of the experiment explained (described below) and practiced for at least one reversal.…”

Accurate mass measurement at enhanced mass‐resolution on a triple quadrupole mass‐spectrometer for the identification of a reaction impurity and collisionally‐induced fragment ions of cabergoline

“…Cabergoline (Scheme ) is a synthetic ergoline derivative with powerful dopaminergic activity that achieves the desired therapeutic effect when administered at low doses. Consequently, systemic plasma levels of cabergoline are extremely low (pg/mL level), and very sensitive techniques are required for detection 1, 2. In a recent quantitative study on cabergoline by LC/ESI‐SRM using a triple quadrupole mass spectrometer with enhanced mass‐resolution capabilities, a detection limit of 50 fg on‐column was achieved which is suitable for pharmacokinetic analysis of this important pharmaceutical 3.…”

Effects of acute prolactin manipulation on sexual drive and function in males

“…1). A one week interval separated each session, with the exception of the low-prolactin session, which was followed by an interval of one month due to long-lasting effects of the prolactin-lowering drug cabergoline in few persons (Andreotti et al 1995).…”

“…Prolactin levels were lowered by oral administration of 0·5 mg of the D2-receptor agonist cabergoline (Dostinex, Pharmacia & Upjohn), which is well-tolerated without significant side effects in this dosage (Andreotti et al 1995). Effects on other, nonprolactinergic endocrine variables have not been reported.…”