A revised role for P-glycoprotein in the brain distribution of dexamethasone, cortisol, and corticosterone in wild-type and ABCB1A/B-deficient mice.
The ABCB1-type multidrug resistance efflux transporter P-glycoprotein (P-gp) has been hypothesized to regulate hypothalamic-pituitary-adrenal axis activity by limiting the access of glucocorticoids to the brain. In vivo systemic administration studies using P-gp-deficient mice have shown increased glucocorticoid entry to the brain compared with wild-type controls. However, these studies did not control for the presence of radiolabeled drug in the capillaries, verify an intact blood-brain barrier, or confirm stability of the glucocorticoids used. In the present study, an in situ brain perfusion method, coupled with capillary depletion and HPLC analyses, was used to quantify brain uptake of [3H]dexa-methasone, [3H]cortisol, and [3H]corticosterone in P-gp-deficient and control mice. A vascular marker was included in these experiments. The results show that brain uptake of [3H]dexamethasone was increased in the frontal cortex, hippocampus, hypothalamus, and cerebellum of P-gp-deficient mice compared with wild-type controls. Brain uptake of [3H]cortisol was increased in the hypothalamus of P-gp-deficient mice compared with wild-type controls, but no differences were detected in other regions. Brain uptake of [3H]corticosterone was not increased in P-gp-deficient mice compared with wild-type controls in any brain areas. After our systemic administration of the same radiolabeled glucocorticoids, HPLC analysis of plasma samples identified additional radiolabeled components, likely to be metabolites. This could explain previous findings from systemic administration studies, showing an effect of P-gp not only for dexamethasone and cortisol, but also for corticosterone. This in situ study highlights the different affinities of dexamethasone, cortisol, and corticosterone for P-gp, and suggests that the entry of the endogenous glucocorticoids into the mouse brain is not tightly regulated by P-gp. Therefore, our current understanding of the role of P-gp in hypothalamic-pituitary-adrenal regulation in mice requires revision.
Mason
Brittany L
BL
Pharmaceutical Science Research Division, King's College London, London, UK.
Pariante
Carmine M
CM
Thomas
Sarah A
SA
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000493:pharmacokinetics*; D005938:Glucocorticoids / Q000493:pharmacokinetics; D006854:Hydrocortisone / Q000493:pharmacokinetics*; D051379:Mice; D008817:Mice, Mutant Strains; D000442:Octanols; D012965:Sodium Chloride; D013395:Sucrose / Q000493:pharmacokinetics; D014316:Tritium
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D002250:Carbon Radioisotopes; D005938:Glucocorticoids; D000442:Octanols; D014316:Tritium; D012965:Sodium Chloride; D013395:Sucrose; D003907:Dexamethasone; C507084:Abcb1b protein, mouse; D003345:Corticosterone; D006854:Hydrocortisone