Thyroxine (T4) transfer from CSF to choroid plexus and ventricular brain regions in rabbit:: Contributory role of P-glycoprotein and organic anion transporting polypeptides

This study investigated the transfer of T-4 from cerebrospinal. fluid (CSF) into the choroid plexuses (CP) and ventricular brain regions, and the role of P-glycoprotein (P-gp), multidrug resistance protein 1 (mrp1) and organic anion transporting polypeptides (oatps). During in vivo ventriculo-cisternal (V-C) perfusion in the anesthetized rabbit (meditomidine hydrochloride 0.5 mg kg(-1), pentobarbitone 10 mg kg(-1) i.v.), I-125-T-4 was perfused continuously into ventricular CSF with reference molecules C-14-mannitol and blue dextran. Over 2 h, 36.9 +/- 4.6% I-125-T-4 was recovered in cisternal CSF. Addition of P-gP substrate verapamil increased CSF I-125-T-4 recovery to 51.4 +/- 2.8%, although mrp1 and oatp substrates had no significant effect. In brain, I-125-T-4 showed greatest accumulation in the CP (1.52 +/- 0.31 ml g(-1)), followed by ventricular regions (caudate putamen, ependyma, hippocampus, 0.05-0.14 ml g(-1)). At the CP, verapamil and probenecid (but not indomethacin) significantly increased I-125-T-4, accumulation, implicating a role for P-gp and oatps. Of other brain regions, all three drugs increased accumulation in caudate putamen 3-5 times, and indomethacin and probenecid increased accumulation in ependyma 4-5 times. The role of P-gp was investigated further in isolated incubated CPs using 5 mu g/ml C219 anti-P-gp antibody. Both I-125-T-4 and H-3-cyclosporin accumulation increased by 80%, suggesting that P-gp is functional in the CP and has a role in removal of T-4. Combined with the in vivo results, these studies suggest that P-gp provides a local homeostatic mechanism, maintaining CSF T-4 levels. We conclude that P-gp and oatps contribute to the transfer of I-125-T-4 between the CSF, CP and brain, hence regulating I-125-T-4 availability in CSF. (c) 2007 Elsevier B.V. All rights reserved.