Endocrine Abstracts

Introduction: Prolactinomas are the most common type of pituitary adenomas(40% of them), representing a significant cause of infertility and hypogonadism. About 20% of patients with prolactinomas don’t respond satisfactory(i.e. resistant) even to high dose dopamine agonist(DA) treatment(>3.5–4.5 mg/week). Worth noticing that there are no clear signs to anticipate this resistance but to stepwise increase the dose of DA. In addition, the etiology of resistance – subject of lively discussions.

Aim: The aim of our study was to assess metabolism and absorption of cabergoline in patients with DA-resistant prolactinomas.

Materials and methods: In patients(n=7) with resistant prolactinomas (no normalization of PRL, no menses with max tolerated dose of cabergoline more than 3.5 mg a week) and 7 patients with normal effect of the drug we conducted a specific pharmacokinetic test: 1) cabergoline was preliminary withdrawn 4 days before the test; 2) at 0900 the blood was taken before and 30-, 60-, 90-, 120-minutes, 4 h, 8 h, 24 hours after taking the cabergoline in a fixed doze of 0.5 mg. The concentration of cabergoline substance in the serum was measured using high-performance liquid chromatography–mass spectrometry method(LC–MS/MS).

Results: We found significant differences in serum cabergoline concentration specific to patients with DA-resistant prolactinomas. It is shown that cabergoline concentration curve in patients with resistance to treatment doesn’t represent expected pharmacokinetic peaks(the growth rate less than +1–50%). The pharmacokinetic curve of 1 resistant patient represented the peak at 30 min point(the growth rate +175%) with subsequent decline to baseline levels. The cabergoline concentration curve of drug-sensitive patient is characterized by an already significant baseline concentration that becomes progressively higher reaching an outstanding peak(the growth rate +112%) at the end of the test period. Differences in cabergoline concentration persist between two groups of patients over time, reaching a maximum by the 120th and 240th minutes. The values of these time points can be used as cut-off for differentiation the etiologies of drug resistance in prolactinomas.

Conclusion: Our pilot results show that the patients with DA-resistant prolactinomas may have a defect(absorption or metabolic abnormalities) in forming an adequate blood concentrations of the drug as well as genetic or receptors alterations. Understanding the underlying mechanisms will allow us to reveal treatment’s resistance at the early diagnostic stage and develop personalized treatment strategy. In vivo pharmacokinetic and metabolomic characteristics of cabergoline can identify a number of causes of resistance to therapy, which has major clinical applications.