Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation.
Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation.
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DOI：
10.12659/aot.928817
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发表时间：
2021-02-26
影响因子：
1.1
通讯作者：
Hirano T
中科院分区：
文献类型：
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作者：
Okihara M;Takeuchi H;Akiyama S;Yoshinaga R;Osato S;Akashi I;Kihara Y;Konno O;Iwamoto H;Oda T;Tanaka S;Unezaki S;Hirano T
依维莫司（EVL）联合他克莫司（TAC）治疗肾移植安全有效。然而，EVL联合TAC的药代动力学和药效学信息有限。我们研究了EVL和TAC在其治疗浓度范围内的药效学药物-药物相互作用。分离22例22 ~ 24岁健康受试者的外周血单个核细胞（PBMC），在EVL和/或TAC存在下与刀豆球蛋白A（ConA）培养4天，并计算PBMC的增殖率。在EVL治疗浓度范围内，TAC促进EVL对PBMC的丝裂原活化增殖的抑制功效。当0.175 ng/mL或更多的TAC与30 ng/mL或更多的EVL组合时，观察到TAC对EVL抑制PBMC的丝裂原活化增殖的抑制效力的拮抗作用。相反，当0.4 ng/mL TAC和10 ng/mL或更高的EVL组合时，观察到EVL对TAC抑制PBMC的丝裂原活化增殖的抑制功效的拮抗作用。EVL和TAC组合对促分裂原活化的PBMC的药效学协同功效在用于肾移植的治疗浓度范围内是明显的。然而，这些药物在高于临床使用的浓度下相互拮抗以抑制活化的PBMC的增殖。
Everolimus (EVL) plus tacrolimus (TAC) therapy is effective and safe in renal transplantation. However, the pharmacokinetic and pharmacodynamic information for EVL combined with TAC is limited. We investigated the pharmacodynamic drug–drug interaction between EVL and TAC at their therapeutic concentration range. Isolated peripheral blood mononuclear cells (PBMCs) from 22 healthy participants aged 22 to 24 years were cultured with concanavalin A (Con A) in the presence of EVL and/or TAC for 4 days, and the proliferation rate of the PBMCs was calculated. TAC promoted the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs at the EVL therapeutic concentration range. When 0.175 ng/mL or more of TAC was combined with 30 ng/mL or more of EVL, the antagonistic effect of TAC on the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs was observed. Conversely, when 0.4 ng/mL TAC and 10 ng/mL or more of EVL were combined, the antagonistic effect of EVL on the inhibitory efficacy of TAC against the mitogen-activated proliferation of PBMCs was observed. The pharmacodynamic synergistic efficacy of EVL and TAC in combination on mitogen-activated PBMCs was evident at the therapeutic concentration range, which is used in renal transplantation. However, these drugs antagonize each other to suppress the proliferation of activated PBMCs at concentrations higher than those clinically used.