Quinagolide

Quinagolide is a selective dopamine D₂-receptor agonist not belonging to the chemical classes of ergot or ergoline compounds. Owing to its dopaminergic action, the drug exerts a strong inhibitory effect on the secretion of the anterior pituitary hormone prolactin, but does not reduce normal levels of other pituitary hormones. In some patients the reduction of prolactin secretion may be accompanied by short-lasting, small increases in plasma growth hormone levels, the clinical significance of which is unknown.

As a specific inhibitor of prolactin secretion with a prolonged duration of action, quinagolide has been shown to be effective and suitable for once-a-day oral treatment of patients presenting with hyperprolactinaemia and its clinical manifestations such as galactorrhoea, oligomenorrhoea, amenorrhoea, infertility and reduced libido.

After oral administration of radiolabelled drug, quinagolide is rapidly and well absorbed. Plasma concentration values obtained by a non-selective radio-immunoassay (RIA), measuring quinagolide together with some of its metabolites, were close to the limit of quantification and gave no reliable information.

The apparent volume of distribution of quinagolide after single oral administration of radiolabelled compound was calculated to be approx. 100 L. For the parent drug, a terminal half-life of 11.5 hours has been calculated under single dose conditions, and of 17 hours at steady state.

Quinagolide is extensively metabolized during its first pass. Studies performed with ³H-labelled quinagolide revealed that more than 95% of the drug is excreted as metabolites. About equal amounts of total radioactivity are found in faeces and urine.

In blood, quinagolide and its N-desethyl analogue are the biologically active but minor components. Their inactive sulphate or glucuronide conjugates represent the major circulating metabolites. In urine, the main metabolites are the glucuronide and sulphate conjugates of quinagolide and the N-desethyl, N,N-didesethyl analogues. In the faeces the unconjugated forms of the three components were found.

The protein binding of quinagolide is approximately 90% and is non-specific.

The results, obtained in pharmacodynamic studies, indicate that with the recommended therapeutic dosage a clinically significant prolactin-lowering effect occurs within 2 hours after ingestion, reaches a maximum within 4 to 6 hours and is maintained for about 24 hours.

A definite dose-response relationship could be established for the duration, but not for the magnitude, of the prolactin-lowering effect which, with a single oral dose of 50 micrograms was close to maximum. Higher doses did not result in a considerably greater effect but prolonged its duration.

Acute toxicity

The LD₅₀ of quinagolide was determined for several species after single oral administration: mice 357 to >500 mg/kg; rats >500 mg/kg; rabbits >150 mg/kg.

Chronic toxicity

Decreased cholesterol levels of treated female rats suggest that quinagolide influences lipid metabolism. Since similar observations have been made with other dopaminergic drugs, a casual relationship with low prolactin levels is assumed. In several chronic studies with rats, enlarged ovaries resulting from an increased number of corpora lutea and, additionally, hydrometra and endometritis were observed. These changes were reversible and reflect the pharmacodynamic effect of quinagolide: suppression of prolactin secretion inhibits luteolysis in rats and thus influences the normal sexual cycle. In humans, however, prolactin is not involved in luteolysis.

Carcinogenic and mutagenic potential

In comprehensive in vitro and in vivo mutagenic studies there was no evidence of a mutagenic effect.

The changes which were observed in carcinogenicity studies reflect the pharmacodynamic activity of quinagolide. The drug modulates the prolactin level as well as, especially in male rats, the level of luteinizing hormone and, in female rodents, the ratio of progesterone to oestrogen.

Long-term studies with high doses of quinagolide revealed Leydig cell tumours in rats and mesenchymal uterine tumours in mice. The incidence of Leydig cell tumours in a carcinogenicity study in rats was increased even at low doses (0.01 mg/kg). These results were without relevance for the therapeutic application in humans since there are fundamental differences between humans and rodents in the regulation of the endocrine system.

Reproductive toxicity

Animal studies in rats and rabbits showed no evidence for embryotoxic or teratogenic effects. The prolactin inhibiting effect led to a decrease of milk production in rats, which was associated with an increased loss of rat pups. Possible post-natal effects of exposure during fetal development (2nd and 3rd trimester) and effects on female fertility are not sufficiently investigated.