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. 2014 Dec 12;7(2):51-7.
doi: 10.3727/215517914X681802. eCollection 2015 Feb 8.

Synergistic Effects of Calcineurin Inhibitors and Steroids on Steroid Sensitivity of Peripheral Blood Mononuclear Cells

Hironori Takeuchi  1 , Hitoshi Iwamoto  2 , Yuki Nakamura  2 , Toshihiko Hirano  3 , Osamu Konno  2 , Yu Kihara  2 , Naokazu Chiba  2 , Takayoshi Yokoyama  2 , Kiminori Takano  2 , Tatsunori Toraishi  4 , Kiyoshi Okuyama  4 , Chie Ikeda  2 , Sachiko Tanaka  3 , Kenji Onda  3 , Akiko Soga  1 , Yukiko Kikuchi  1 , Takashi Kawaguchi  1 , Shigeyuki Kawachi  2 , Sakae Unezaki  1 , Motohide Shimazu  2
Affiliations

Synergistic Effects of Calcineurin Inhibitors and Steroids on Steroid Sensitivity of Peripheral Blood Mononuclear Cells

Hironori Takeuchi et al. Cell Med. .

Abstract

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.

Keywords: Calcineurin inhibitors (CNIs); Cyclosporine (CYA); Pharmacodynamic interaction; Steroid sensitivity; Tacrolimus (TAC).

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Figures

Figure 1
Figure 1
Comparison of IC50 of COR before and after CNI administration in TAC- and CYA-administered renal transplant recipients. The dots represent the maximum and minimum values, while the squares represent the interquartile range, and the line represents the median value. COR, cortisol; CNI, calcineurin inhibitor; TAC, tacrolimus; CYA: cyclosporine.
Figure 2
Figure 2
Comparison of IC50 of MPSL before and after CNI administration in TAC- and CYA-administered renal transplant recipients. The dots represent the maximum and minimum values, while the squares represent the interquartile range, and the line represents the median value. MPSL, methylprednisolone.
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