CNRS UMR 8612, Université de Paris Sud XI, Faculté de Pharmacie, 5 rue J.B. Clément, 92296 Châtenay-Malabry, France; Post graduation Program in Pharmaceutical Sciences, Quality Control Laboratory, Universidade Federal de Santa Catarina, J/K 207, 88040-900 Florianópolis, SC, Brazil.
CNRS UMR 8612, Université de Paris Sud XI, Faculté de Pharmacie, 5 rue J.B. Clément, 92296 Châtenay-Malabry, France.
Eur J Pharm Sci. 2018 Aug 30;121:236-242. doi: 10.1016/j.ejps.2018.05.030. Epub 2018 May 31.
Recently, many efforts are taken to identify the intestinal uptake and efflux transporters since they are responsible for the absorption of many drugs as their interactions. Norfloxacin (NFX) is a fluoroquinolone that presents low solubility and low permeability, and as a consequence, low bioavailability. In this context, the aim of this study is evaluate for the first time the intestinal permeability mechanisms of NFX by Ussing chamber model. The low permeation of NFX at low temperature, where the efflux pumps are not active, reveals that NFX permeation is transporter-dependent. The permeation study at different level of intestine demonstrated that NFX passage is in the decrescent order: ileum > jejunum > duodenum > colon, probably attributed to transporters that are expressed differently along the intestinal tract. NFX intestinal flow was evaluated in the presence of many inhibitors and substrates to identify the uptake and efflux transporters implicate in NFX permeability mechanism. It could be observed that BCRP and MRPs are involved in the NFX efflux and PEPT1, PMAT and OCT in the NFX uptake transport. Furthermore, this work revealed that NFX has itself an affinity for OCTN and OATP, demonstrating that NFX could inhibit these transporters and influence the absorption of other drugs. The updated description of NFX intestinal permeability factors could contribute to the development of rational pharmaceutical formulations that could circumvent the efflux problems and consequently improve NFX biopharmaceutical properties and avoid drug-drug interactions.
最近，人们做出了许多努力来鉴定肠道摄取和外排转运体，因为它们负责许多药物的吸收，而这些药物的相互作用则是由于转运体。诺氟沙星（NFX）是一种氟喹诺酮类药物，其溶解性和渗透性都较低，因此生物利用度也较低。在这种情况下，本研究的目的首次是通过 Ussing 室模型来评估 NFX 的肠道通透性机制。在低温下，NFX 的低渗透性，其中外排泵不活跃，这表明 NFX 的渗透是依赖转运体的。在不同肠道水平的渗透研究表明，NFX 的通过顺序呈递减：回肠>空肠>十二指肠>结肠，这可能归因于沿肠道不同表达的转运体。在存在许多抑制剂和底物的情况下评估了 NFX 的肠道流量，以鉴定参与 NFX 渗透机制的摄取和外排转运体。可以观察到，BCRP 和 MRPs 参与了 NFX 的外排，PEPT1、PMAT 和 OCT 参与了 NFX 的摄取转运。此外，这项工作表明 NFX 本身对 OCTN 和 OATP 具有亲和力，表明 NFX 可以抑制这些转运体并影响其他药物的吸收。对 NFX 肠道通透性因素的最新描述可能有助于开发合理的药物制剂，这些制剂可以避免外排问题，从而提高 NFX 的生物制药特性并避免药物相互作用。
