Shin-Ichi Akanuma1, Myeongrae Han2, Yuka Murayama2, Yoshiyuki Kubo2, Ken-Ichi Hosoya3. 1. Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. akanumas@pha.u-toyama.ac.jp. 2. Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. 3. Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. hosoyak@pha.u-toyama.ac.jp.
Abstract
PURPOSE: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS: The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 μM and 89.2 μM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.
PURPOSE: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS: The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 μM and 89.2 μM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.
Authors: Thomas C Baghai; Pierre Blier; David S Baldwin; Michael Bauer; Guy M Goodwin; Kostas N Fountoulakis; Siegfried Kasper; Brian E Leonard; Ulrik F Malt; Dan J Stein; Marcio Versiani; Hans-Jürgen Möller Journal: Eur Arch Psychiatry Clin Neurosci Date: 2011-11-15 Impact factor: 5.270
Authors: A John Rush; Madhukar H Trivedi; Stephen R Wisniewski; Andrew A Nierenberg; Jonathan W Stewart; Diane Warden; George Niederehe; Michael E Thase; Philip W Lavori; Barry D Lebowitz; Patrick J McGrath; Jerrold F Rosenbaum; Harold A Sackeim; David J Kupfer; James Luther; Maurizio Fava Journal: Am J Psychiatry Date: 2006-11 Impact factor: 18.112