In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein

Abstract

Objectives Antidepressants need to penetrate the blood-brain barrier (BBB) to exert their functions in the central nervous system. Breast cancer resistance protein (BCRP), an efflux transporter abundantly expressed in the BBB, prevents the accumulation of many drugs in the brain. This study aimed to identify whether five commonly used antidepressants (sertraline, duloxetine, fluoxetine, amitriptyline and mirtazapine) are BCRP substrates. Methods A combination of bidirectional transport and intracellular accumulation experiments was conducted on BCRP-overexpressing MDCKII and wildtype (WT) cells, and in situ brain perfusion was conducted in rats. Key findings The bidirectional transport study revealed that the net efflux ratio (NER) of sertraline reached 2.08 but decreased to 1.06 when co-incubated with Ko143, a selective BCRP inhibitor. Conversely, the other four antidepressants did not appear to be BCRP substrates, due to their low NER values (<1.5). The accumulation of sertraline in MDCKII-BCRP cells was significantly lower than that in MDCKII-WT cells. The presence of Ko143 significantly increased the sertraline accumulation in MDCKII-BCRP cells but not in MDCKII-WT cells. Brain perfusion showed that the permeability of 1 and 5 lM sertraline was significantly higher in the presence of Ko143. Conclusions Taken together, BCRP is involved in sertraline efflux.

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

“…Breast cancer resistant protein (BCRP) is an ABC transporter expressed in different tissues, including the brain epithelial cells, and may be responsible for the low bioavailability of several psychotropics. A recent study showed that sertraline is a BCRP substrate along with its P-gp inhibiting properties ( Feng et al, 2019 ). Venlafaxine dose-dependently induces the BCRP expression ( Bachmeier et al, 2011 ).…”

Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

“…Ko143 and MK-571 have been widely used as the chemical inhibitor of BCRP and MRP4 in vitro and in vivo (Bertollotto et al, 2018;Drennen et al, 2018;Kanda et al, 2018;Feng et al, 2019). Hence, we have selected and used Ko143 and MK-571 to inhibit the transport activities of BCRP and MRPs in our study.…”

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression

“…From another point of view, it is important to bear in mind that several antidepressant drugs are known as substrates of efflux transmembrane ATP-binding cassette (ABC) proteins, including P-glycoprotein (P-gp; ABCB1; MDR1) [55][56][57][58][59] and Breast Cancer Resistant Protein (BCRP; ABCG2) [60]. These transporters are expressed in several tissues, namely the intestine, kidney, liver, and blood-brain barrier (BBB).…”

“…The aforementioned results regarding P-gp and BCRP in the intestine suggest that their substrates may have higher bioavailability if administered in the morning, when the expression levels of efflux transporters are lower. Although sertraline is a known BCRP substrate [60], there are no studies in literature concerning the influence of the circadian BCRP oscillations on its intestinal absorption.…”