Zakeri-Milani Parvin, Valizadeh Hadi, Islambulchilar Ziba, Damani Sanaz, Mehtari Maryam
Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Arzneimittelforschung. 2008;58(4):188-92. doi: 10.1055/s-0031-1296491.
The primary endpoint of this study was to determine the intestinal permeability of ciclosporin (cyclosporine A, CsA, CAS 59865-13-3) using the single-pass intestinal perfusion technique (SPIP) and a range of concentrations in rats. The second objective was to assess the quantitative contribution of P-glycoprotein (P-gp)-mediated efflux in limiting the oral bioavailability of CsA using erythromycin (Ery, CAS 114-07-8) as an inhibitor of P-gp efflux transporter. A solution containing CsA and phenol red either in the presence or in the absence of Ery as a P-gp inhibitor was perfused through a cannulated jejunal segment in rats. Outlet samples were collected every 10 min in micro tubes up to 90 min. Samples were analyzed using a modified reverse phase HPLC method. The mean effective permeability coefficients (Peff) of CsA in concentrations of 5, 10, 15 and 20 micromol/L in the perfusion solution were found to be 2.21 (+/- 0.26) x 10(-4) cm/s, 3.34 (+/- 1.29) x 10(-4) cm/s, 3.12 (+/- 0.23) x 10(-4) cm/s and 2.73 (+/- 0.28) x 10(-4) cm/s, respectively. The corresponding values in the presence of Ery were found to be 3.96 (+/- 1.04) x 10(-4) cm/s, 5.34 (+/- 1.29) x 10(-4) cm/s, 3.72 (+/- 0.21) x 10(-4) cm/s and 4.41 (+/- 0.89) x 10(-4) cm/s, respectively. The two-tailed Student's t-test showed that the intestinal permeability of CsA was significantly increased by Ery in all four CsA concentrations used (P < 0.05). However, there was no significant difference between the Peff values of CsA in different concentrations, indicating that the CsA permeation was independent of the concentration. Therefore it is concluded that at least some part of the observed clinical interaction between Ery and CsA is due to the interaction in absorption level.
本研究的主要终点是使用单通道肠道灌注技术（SPIP）和一系列浓度的环孢素（环孢素A，CsA，CAS 59865-13-3）来测定大鼠肠道对其的通透性。第二个目标是评估P-糖蛋白（P-gp）介导的外排在限制CsA口服生物利用度方面的定量贡献，使用红霉素（Ery，CAS 114-07-8）作为P-gp外排转运体的抑制剂。将含有CsA和酚红的溶液，在有或没有作为P-gp抑制剂的Ery存在的情况下，通过大鼠空肠插管段进行灌注。每隔10分钟在微量管中收集流出物样品，直至90分钟。使用改良的反相高效液相色谱法分析样品。发现灌注溶液中浓度为5、10、15和20微摩尔/升的CsA的平均有效渗透系数（Peff）分别为2.21（±0.26）×10⁻⁴厘米/秒、3.34（±1.29）×10⁻⁴厘米/秒、3.12（±0.23）×10⁻⁴厘米/秒和2.73（±0.28）×10⁻⁴厘米/秒。在有Ery存在的情况下，相应的值分别为3.96（±1.04）×10⁻⁴厘米/秒、5.34（±1.29）×10⁻⁴厘米/秒、3.72（±0.21）×10⁻⁴厘米/秒和4.41（±0.89）×10⁻⁴厘米/秒。双尾学生t检验表明，在所有使用的四种CsA浓度下，Ery均显著增加了CsA的肠道通透性（P < 0.05）。然而，不同浓度的CsA的Peff值之间没有显著差异，表明CsA的渗透与浓度无关。因此得出结论，观察到的Ery和CsA之间的临床相互作用至少部分是由于吸收水平的相互作用。
