The temporal profile of calcineurin inhibition by cyclosporine in vivo
The temporal profile of calcineurin inhibition by cyclosporine in vivo
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DOI：
10.1097/00007890-199911150-00023
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发表时间：
1999-11-15
期刊：
影响因子：
6.2
通讯作者：
Noujaim, J
中科院分区：
文献类型：
--
作者：
Halloran, PF;Helms, LMH;Noujaim, J
环孢霉素（CsA）通过抑制磷酸酶钙调神经磷酸酶（CN）发挥作用，但在体内抑制的时间过程和程度尚不清楚。我们研究了单次口服CsA剂量对人和小鼠体内CN活性的影响。在人体中，测定CsA给药后12小时内（第二次给药前）患者的全血和血液白细胞中的CsA水平和CN活性。小鼠灌胃给予CsA（12.5 ~ 200 mg/kg）后，测定血和组织（脾、肾）中CsA浓度，并测定脾、肾中CN活性。在人体中，1-2小时时800-2285 μ g/L的CsA峰值水平产生70-96%的CN抑制。抑制与CsA水平的升高和降低密切相关，在采样时间没有观察到滞后。重复给药显示出与首次给药相似的CN抑制，没有显著的适应。在小鼠中，CsA在血液、脾脏和肾脏中在1小时达到峰值，脾脏和肾脏中的浓度高于血液。CN抑制作用与CsA浓度/剂量密切相关，且肾脏的CN抑制作用大于脾脏。因此，CsA诱导部分CN抑制，其直接随血液和组织水平而变化，并且由于较高的药物蓄积，在某些组织中可能更大。CsA在肾内的高浓度和CN抑制可能与肾毒性有关。
Background, Cyclosporine (CsA) acts by inhibiting the phosphatase calcineurin (CN), but the time course and extent of inhibition in vivo are unknown. We examined the effect of single oral CsA doses on CN activity in humans and mice in vivo.Methods. In humans, blood CsA levels were determined and CN activity was measured in whole blood and in blood leukocytes of patients up to 12 hr after CsA dosing (just before the second dose). Samples were collected from patients receiving a first single dose (2.5 mg/kg), and up to 14 days later after repeated dosing, In mice, after CsA dosing (12.5-200 mg/kg) by oral gavage, CsA levels in blood and tissue (spleen, kidney) were determined and CN activity was measured in spleen and kidney.Results. In humans, peak CsA levels of 800-2285 mu g/L at 1-2 hr produced 70-96% CN inhibition. Inhibition correlated closely with the rise and fall of CsA levels with no observable lag at the times sampled, Repeated doses showed similar CN inhibition to first dose, with no significant adaptation, In mice, CsA peaked at 1 hr in blood, spleen, and kidney, with higher concentrations in spleen and kidney than in blood. CN inhibition closely followed CsA concentrations/doses, and was greater in kidney than spleen.Conclusion. Thus CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation. The high CsA concentrations and CN inhibition in kidney may be relevant to nephrotoxicity.