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

Abstract

This study investigated the transfer of T4 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.), 125I-T4 was perfused continuously into ventricular CSF with reference molecules 14C-mannitol and blue dextran. Over 2 h, 36.9+/-4.6% 125I-T4 was recovered in cisternal CSF. Addition of P-gp substrate verapamil increased CSF 125I-T4 recovery to 51.4+/-2.8%, although mrp1 and oatp substrates had no significant effect. In brain, 125I-T4 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 125I-T4 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 microg/ml C219 anti-P-gp antibody. Both 125I-T4 and 3H-cyclosporin accumulation increased by 80%, suggesting that P-gp is functional in the CP and has a role in removal of T4. Combined with the in vivo results, these studies suggest that P-gp provides a local homeostatic mechanism, maintaining CSF T4 levels. We conclude that P-gp and oatps contribute to the transfer of 125I-T4 between the CSF, CP and brain, hence regulating 125I-T4 availability in CSF.