Predictors of neuropsychiatric side effects of dopamine-agonist therapy in patients with prolactinomas
A. Athanasoulia, C. Sievers, M. Ising, A. Brockhaus, A. Yassouridis, G. Stalla & M. Uhr
Introduction: Treatment with dopamine agonists in patients with prolactinomas and Parkinsons disease is associated with central side effects. Central side effects may depend on a substances ability to pass the blood-brain barrier which can be actively controlled by transporter molecules such as the P-glycoprotein encoded by the ABCB1 gene.
Aim of the study: To determine whether cabergoline is transported by the P-glycoprotein and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with prolactinomas.
Methods: i) In an experimental mouse model lacking the homologs of the human ABCB1 gene (abcb1ab double-knockout mice), we examined whether cabergoline is a substrate of P-glycoprotein. ii) In a human casecontrol study, we investigated the association of four selected ABCB1 gene SNPs (rs1045642, rs2032582, rs2032583, rs2235015) with the occurrence of central side effects under cabergoline therapy in 92 prolactinoma patients treated at the Max Planck Institute of Psychiatry in Munich.
Results: i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared to their wild-type littlemates implying that cabergoline is indeed a substrate of the transporter P-glycoprotein at the bloodbrain barrier level. ii) In humans, we found significant negative associations for the C-carriers and heterozygous CT-individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness under cabergoline. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found.
Discussion/conclusion: This is the first study demonstrating that individual ABCB1 gene polymorphisms reflecting a different expression and function of P-glycoprotein could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalized therapy in patients with prolactinomas.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.