Prolactin Elevations and Permeability Glycoprotein

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Objective: To examine the role of permeability glycoprotein (P-gp) and its substrates in the mechanism of hyperprolactinemia.

Data Sources: PubMed and Google Scholar were queried with the search term permeability glycoprotein crossed with antipsychotic, neuroleptic, prolactin, risperidone, paliperidone, and amisulpride. The searches were performed in early 2018 with no date restrictions.

Study Selection: All references cited in PubMed were examined (108), but only the first 40 references of each search in Google Scholar (total of approximately 30,000 hits) for a total of 240 were examined. Approximately 100 references were felt to be relevant.

Data Extraction: Information regarding mechanism of action and clinical relevance was extracted as appropriate for the discussion.

Results: Risperidone, paliperidone, and amisulpride are associated with higher prolactin levels than would be anticipated from striatal dopamine receptor occupancy studies. This elevation occurs because the levels of these antipsychotics are higher in the anterior pituitary than in parts of the brain protected by the blood-brain barrier and P-gp. P-gp has high affinity to all these antipsychotics and selectively removes them from the brain and concentrates them in the blood draining the hypothalamus, allowing greater dopamine receptor blockade in the cells in the anterior pituitary that produce prolactin.

Conclusions: The anatomy of the portal circulation, the presence of P-gp, and the high affinity of this protein to risperidone, paliperidone, and amisulpride all conspire to concentrate the antipsychotic concentration in the anterior pituitary to levels higher than in other parts of the brain, with consequent increase of prolactin above expectations.

Prim Care Companion CNS Disord 2019;21(3):18nr02412

https://doi.org/10.4088/PCC.18nr02412