Blood-brain barrier transport of H1-antagonist Ebastine and its metabolitecarebastine

The transport mechanism of the non-sedative Hi-antagonist ebastine and its first-pass carboxylic acid metabolite carebastine at the blood-brain barrie r (BBB) was studied. In rats, the brain uptake index (BUI) value of [C-14]c arebastine was significantly lower than that of [C-14]ebastine. The BUI val ue of [C-14]carebastine was greatly increased by the addition of non-labele d carebastine. The steady-state uptake of [C-14]carebastine by P-glycoprote in-over expressing K562/ADM cells was: significantly lower than that by the ir parental drug-sensitive cell line: K562. The decreased steady-state upta ke of [C-14]carebastine by K562/ADM cells was reversed by verapamil. Steady -state uptake of [C-14]carebastine by primary cultured bovine brain capilla ry endothelial cells (bovine BCECs) was increased in the presence of metabo lic inhibitors and verapamil. Non-labeled carebastine increased the steady- state uptake of a P-glycoprotein substrate, [H-3]vincristine, by bovine BCE Cs, The initial uptake of [H-3]mepyramine by bovine BCECs and RBEC1 (an imm ortalized cell line from rat brain capillary endothelial cells) was strongl y inhibited by ebastine, while zwitterionic carebastine was slightly inhibi tory. The values of brain-to-plasma unbound concentration ratio (Kp,f) in m dr1a(-1-) mice were increased 5.3-fold and 4.2-fold for [C-14]ebastine and for [C-14]carebastine, respectively, compared with those in mnr1a(+/+) mice . Non-radiolabeled carebastine increased the Kp.f values of [C-14]carebasti ne in both types of mice. In conclusion, carebastine was shown to be a subs trate for P-glyeoprotein-mediated efflux from the brain at the BBB. A secon d efflux system may also be involved. The relatively low affinity of the up take transport system for carebastine also limits the brain distribution of ebastine/carebastine.