Nephrology Department and Laboratory of Experimental Nephrology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
J Pharm Pharm Sci. 2012;15(3):407-19. doi: 10.18433/j3g30b.
P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different T-cell subsets.
Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4+ and CD8+ subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction.
Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8+ subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8+ T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8+ T-cell subset.
Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8+ T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens.
P-糖蛋白（Pgp）是 ABC 转运体家族的一员，可作为外排泵将物质穿过细胞膜运输，将药物从细胞内排出。Pgp 在几种药物的药代动力学中起着关键作用。在此，我们研究了免疫抑制剂对 Pgp 功能的影响，评估了不同 T 细胞亚群中罗丹明 123（Rho123）的摄取和外排。
使用环孢素（CsA）、雷帕霉素（Rapa）和他克莫司（Tac）等不同的免疫抑制剂，评估其对健康志愿者主要 T 细胞亚群 Pgp 功能的体外影响。我们通过流式细胞术测量 CD4+和 CD8+亚群中 Rho123 的摄取、外排和外排动力学。通过异体混合淋巴细胞反应测量 T 细胞增殖和细胞因子分泌来评估抗原特异性记忆 T 细胞反应。
与未处理组和其他免疫抑制剂相比，CsA 和 CsA+Rapa 处理组的 Rho123 摄取显著降低，在两种 T 细胞亚群中均如此。与其他免疫抑制剂相比，CsA 和 CsA+Rapa 组的 Pgp 活性也降低，但仅在 CsA 组的 CD8+亚群中具有统计学意义。所有免疫抑制剂和特异性 Pgp 抑制剂 PSC833 均使 Rho123 的 Pgp 快速外排，在 CD8+T 细胞中更为明显。所有免疫抑制剂和特异性 Pgp 抑制剂 PSC833 均减弱抗原刺激的 T 细胞增殖，尤其是 CD8+T 细胞亚群。
我们的数据表明，小分子免疫抑制剂，尤其是 CsA，抑制 Pgp 活性和 T 细胞功能，而 CD8+T 细胞对此效应更为敏感。这些发现支持在设计联合免疫抑制方案时考虑 Pgp 的重要性。
