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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in adrenalectomized rats.
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Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in adrenalectomized rats.

机译：泼尼松龙和西罗莫司之间在肾上腺切除的大鼠中的药代动力学和药物免疫动力学相互作用。

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Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds acting through different mechanisms with moderate synergism found in vitro. Both drugs are metabolized partly by CYP3A enzymes. After i.v. administration of placebo, Pred (5 mg/kg), SIR (1 mg/kg), or Pred with SIR (5 and 1 mg/kg doses) to adrenalectomized male rats, Pred plasma and SIR whole blood concentrations were followed for 48 hr along with circulating T-helper and T-cytotoxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe responses to these drugs, alone or combined. An interactive two-stage population analysis showed no modification in drug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat++ variability: 11%) and significantly increased with weight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight-power proportionality. In vitro metabolism studies showed no significant inhibition of Pred or prednisone CYP3A metabolism by SIR (50 microM), but this pathway accounted for less than 5% of Pred metabolism. Pred decreased numbers of T-helper lymphocytes with a mean IC50 of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymphocyte numbers with a mean IC50 of 52.2 nM (24%) for T-helper and 28.8 nM (51%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte trafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC50 of 1.08 nM (38%). SIR, after a transduction step, inhibited proliferation with a mean IC50 of 1.00 nM (26%). Responses measured after drug coadministration were reasonably quantitated by addition of single drug effects. Since, at pharmacologic concentrations in rats, Pred and SIR did not interact in their PK but synergistically or additively interact in their dynamics, their joint therapeutic use is promising. The adrenalectomized rat may be a suitable animal model to characterize drug effects on lymphocyte trafficking and reactivity.
机译：泼尼松龙（Pred）和西罗莫司（SIR）是免疫抑制化合物，通过体外发现的具有不同协同作用的不同机制起作用。两种药物均部分被CYP3A酶代谢。在i.v.之后给肾上腺切除的雄性大鼠服用安慰剂，Pred（5 mg / kg），SIR（1 mg / kg）或Pred与SIR（5和1 mg / kg剂量），对Pred血浆和SIR全血浓度进行48小时以及循环中的T辅助细胞和T细胞毒性细胞计数。离体全血淋巴细胞增殖标志着宿主反应性。扩展的间接PK / PD模型用于描述对这些药物的反应，单独或联合使用。交互式的两阶段人群分析显示，药物PK没有改变。 Pred血浆平均清除率为0.655 L / hr（inter ++变异性：11％），并随体重而显着增加。 SIR全血的平均分布和清除量分别为5.6升（62％）和0.28升/小时（32％），并且动物鳞屑显示出重量-功率比例。体外代谢研究显示，SIR（50 microM）对Pred或强的松CYP3A代谢没有显着抑制作用，但该途径占Pred代谢的少于5％。减少T辅助淋巴细胞的数量，单独使用IC时平均IC50为37.8 nM（21％），使用SIR时则为12.3 nM（130％）。 T细胞毒性淋巴细胞的结果相似。 SIR增加了淋巴细胞数量，T辅助细胞的平均IC50为52.2 nM（24％），T细胞毒性细胞的平均IC50为28.8 nM（51％）。考虑到药物对淋巴细胞运输的影响，Pred直接抑制离体淋巴细胞增殖，平均IC50为1.08 nM（38％）。在转导步骤后，SIR抑制增殖，平均IC50为1.00 nM（26％）。药物共同给药后测得的反应通过添加单一药物作用进行合理定量。由于在大鼠的药理浓度下，Pred和SIR在其PK中不相互作用，但在其动力学中协同或累加相互作用，因此它们的联合治疗用途很有希望。肾上腺切除的大鼠可能是合适的动物模型，用于表征药物对淋巴细胞运输和反应性的影响。

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