The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone.
In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone. In vivo, a tracer dose of [(3)H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a (-/-) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of [(3)H]prednisolone. Human Pgp does not transport all steroids, as cortexolone was not transported at all and aldosterone was only weakly transported. The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.
Karssen
A M
AM
Divisions of Medical Pharmacology and Pharmacology, Leiden/Amsterdam Center for Drug Research/Leiden University Medical Centre, PO Box 9502, Leiden, 2300 RA, The Netherlands. Karssen@LACDRR.LeidenUniv.nl
Meijer
O C
OC
van der Sandt
I C J
IC
De Boer
A G
AG
De Lange
E C M
EC
De Kloet
E R
ER
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000315:Adrenalectomy; D000339:Affect / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000502:physiology*; D002460:Cell Line; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005938:Glucocorticoids / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011239:Prednisolone / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D013552:Swine; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D005938:Glucocorticoids; D011804:Quinolines; C095179:zosuquidar trihydrochloride; D011239:Prednisolone