Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood-brain barrier permeability.
The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ≥ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ≤ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Fionn E
FE
O'Brien
Gerard
G
Clarke
Timothy G
TG
Dinan
John F
JF
Cryan
Brendan T
BT
Griffin
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000639:Amitriptyline / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D004285:Dogs; D000068736:Duloxetine Hydrochloride; D005473:Fluoxetine / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008803:Mianserin / Q000031:analogs & derivatives / Q000378:metabolism; D000078785:Mirtazapine; D013876:Thiophenes / Q000378:metabolism; D014162:Transfection
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents; D013876:Thiophenes; D005473:Fluoxetine; D000639:Amitriptyline; D008803:Mianserin; D000068736:Duloxetine Hydrochloride; D000078785:Mirtazapine; D007099:Imipramine