Takeuchi Hironori, Iwamoto Hitoshi, Nakamura Yuki, Hirano Toshihiko, Konno Osamu, Kihara Yu, Chiba Naokazu, Yokoyama Takayoshi, Takano Kiminori, Toraishi Tatsunori, Okuyama Kiyoshi, Ikeda Chie, Tanaka Sachiko, Onda Kenji, Soga Akiko, Kikuchi Yukiko, Kawaguchi Takashi, Kawachi Shigeyuki, Unezaki Sakae, Shimazu Motohide
Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
† The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
Cell Med. 2014 Dec 12;7(2):51-7. doi: 10.3727/215517914X681802. eCollection 2015 Feb 8.
The steroid receptor (SR) complex contains FKBP51 and FKBP52, which bind to tacrolimus (TAC) and cyclophilin 40, which, in turn, bind to cyclosporine (CYA); these influence the intranuclear mobility of steroid-SR complexes. Pharmacodynamic interactions are thought to exist between steroids and calcineurin inhibitors (CNIs) on the SR complex. We examined the effect of CNIs on steroid sensitivity. Methylprednisolone (MPSL) sensitivity was estimated as the concentration inhibiting mitosis in 50% (IC50) of peripheral blood mononuclear cells and as the area under the MPSL concentration-proliferation suppressive rate curves (CPS-AUC) in 30 healthy subjects. MPSL sensitivity was compared between the additive group (AG) as the MPSL sensitivity that was a result of addition of the proliferation suppressive rate of CNIs to that of MPSL and the mixed culture group (MCG) as MPSL sensitivity of mixed culture with both MPSL and CNIs in identical patients. IC50 values of MPSL and cortisol sensitivity were examined before and 2 months after CNI administration in 23 renal transplant recipients. IC50 and CPS-AUC values of MPSL were lower in the MCG than in the AG with administration of TAC and CYA. The CPS-AUC ratio of MCG and AG was lower in the TAC group. IC50 values of MPSL and cortisol tended to be lower after administration of TAC and CYA, and a significant difference was observed in the IC50 of cortisol after TAC administration. Steroid sensitivity increased with both TAC and CYA. Furthermore, TAC had a greater effect on increasing sensitivity. Thus, concomitant administration of CNIs and steroids can increase steroid sensitivity.
类固醇受体（SR）复合物包含FKBP51和FKBP52，它们与他克莫司（TAC）结合，而亲环蛋白40又与环孢素（CYA）结合；这些因素影响类固醇 - SR复合物的核内移动性。类固醇与钙调神经磷酸酶抑制剂（CNIs）在SR复合物上被认为存在药效学相互作用。我们研究了CNIs对类固醇敏感性的影响。在30名健康受试者中，甲基强的松龙（MPSL）敏感性通过抑制外周血单个核细胞有丝分裂的50%浓度（IC50）以及MPSL浓度 - 增殖抑制率曲线下面积（CPS - AUC）来评估。将添加组（AG）（即MPSL敏感性为MPSL增殖抑制率与CNIs增殖抑制率相加的结果）与混合培养组（MCG）（即同一患者中MPSL与CNIs混合培养时的MPSL敏感性）的MPSL敏感性进行比较。在23名肾移植受者中，检测了CNI给药前及给药2个月后MPSL和皮质醇敏感性的IC50值。给予TAC和CYA后，MCG中MPSL的IC50和CPS - AUC值低于AG。TAC组中MCG与AG的CPS - AUC比值更低。给予TAC和CYA后，MPSL和皮质醇的IC50值趋于降低，且给予TAC后皮质醇的IC50有显著差异。TAC和CYA均可增加类固醇敏感性。此外，TAC对增加敏感性的作用更大。因此，CNIs与类固醇联合给药可增加类固醇敏感性。
