title: Synergistic Effects of Calcineurin Inhibitors and Steroids on Steroid Sensitivity of Peripheral Blood Mononuclear Cells.
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.
authors: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Hironori
authors: H
authors: Takeuchi
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Hitoshi
authors: H
authors: Iwamoto
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Yuki
authors: Y
authors: Nakamura
authors: ‡ Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Toshihiko
authors: T
authors: Hirano
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Osamu
authors: O
authors: Konno
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Yu
authors: Y
authors: Kihara
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Naokazu
authors: N
authors: Chiba
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Takayoshi
authors: T
authors: Yokoyama
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Kiminori
authors: K
authors: Takano
authors: § Department of Pharmaceutics,Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Tatsunori
authors: T
authors: Toraishi
authors: § Department of Pharmaceutics,Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Kiyoshi
authors: K
authors: Okuyama
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Chie
authors: C
authors: Ikeda
authors: ‡ Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Sachiko
authors: S
authors: Tanaka
authors: ‡ Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Kenji
authors: K
authors: Onda
authors: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Akiko
authors: A
authors: Soga
authors: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Yukiko
authors: Y
authors: Kikuchi
authors: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Takashi
authors: T
authors: Kawaguchi
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Shigeyuki
authors: S
authors: Kawachi
authors: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo , Japan.
authors: Sakae
authors: S
authors: Unezaki
authors: † The Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University , Hachioji, Tokyo , Japan.
authors: Motohide
authors: M
authors: Shimazu
keywords: Calcineurin inhibitors (CNIs); Cyclosporine (CYA); Pharmacodynamic interaction; Steroid sensitivity; Tacrolimus (TAC)