Fukumori Shiro, Murata Toshiya, Takaai Mari, Tahara Katsutoshi, Taguchi Masato, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Drug Metab Pharmacokinet. 2008;23(5):373-8. doi: 10.2133/dmpk.23.373.
The aim of this study was to investigate the involvement of the peptide transporter for absorption of levofloxacin in Caco-2 cells. To evaluate the activity of apical and basolateral peptide transport, we first performed pharmacokinetic analysis of transcellular transport of glycylsarcosine (Gly-Sar) in cell monolayers grown on porous membrane filters. Transcellular transport of Gly-Sar at the medium pH 6 was greater in the apical-to-basolateral direction than in the opposite direction. Influx clearance of Gly-Sar at the apical membrane was much greater than basolateral influx and efflux clearance, indicating that the apical peptide transporter plays an important role in directional transcellular transport of the dipeptide across Caco-2 cell monolayers. We then evaluated the effect of various compounds on the uptake of Gly-Sar and levofloxacin at the apical membrane of Caco-2 cells. The apical uptake of [3H]Gly-Sar was significantly inhibited by Ala-Ala, Gly-Sar, and also levofloxacin, whereas that of [14C]levofloxacin was not inhibited by Ala-Ala and Gly-Sar. On the other hand, the apical uptake of [14C]levofloxacin was inhibited by nicotine, enalapril, fexofenadine, and L-carnitine. These findings indicated that the apical uptake transporter of levofloxacin is distinct from the peptide transporter in Caco-2 cells.
本研究的目的是调查肽转运体在Caco-2细胞中对左氧氟沙星吸收的参与情况。为了评估顶端和基底外侧肽转运的活性，我们首先对生长在多孔膜滤器上的细胞单层中甘氨酰肌氨酸（Gly-Sar）的跨细胞转运进行了药代动力学分析。在培养基pH值为6时，Gly-Sar在顶端到基底外侧方向的跨细胞转运大于相反方向。Gly-Sar在顶端膜的流入清除率远大于基底外侧的流入和流出清除率，表明顶端肽转运体在二肽跨Caco-2细胞单层的定向跨细胞转运中起重要作用。然后，我们评估了各种化合物对Caco-2细胞顶端膜上Gly-Sar和左氧氟沙星摄取的影响。[3H]Gly-Sar的顶端摄取受到丙氨酰丙氨酸、Gly-Sar以及左氧氟沙星的显著抑制，而[14C]左氧氟沙星的顶端摄取不受丙氨酰丙氨酸和Gly-Sar的抑制。另一方面，[14C]左氧氟沙星的顶端摄取受到尼古丁、依那普利、非索非那定和L-肉碱的抑制。这些发现表明，左氧氟沙星的顶端摄取转运体与Caco-2细胞中的肽转运体不同。
