Distinct inhibitory effects of tacrolimus and cyclosporin A on calcineurin phosphatase activity
Distinct inhibitory effects of tacrolimus and cyclosporin A on calcineurin phosphatase activity
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DOI：
10.1124/jpet.104.074930
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Inui, K
中科院分区：
文献类型：
--
作者：
Fukudo, M;Yano, I;Inui, K
我们比较了钙调磷酸酶抑制剂他克莫司和环孢素A在大鼠中的药效学特性，以阐明两种药物在临床情况下的不同治疗药物监测策略。在各种组织提取物中，在胸腺、心脏、肝脏、脾脏、肾脏和睾丸中，环孢素A对钙调神经磷酸酶活性的抑制作用显著大于相同药物浓度（1 μ M）的他克莫司（p < 0.05）。在大鼠中单次或重复给予每种药物后，检查血液浓度和全血中钙调神经磷酸酶活性的时间曲线。单次给药他克莫司或环孢素A后，观察到抑制作用的实质性时间延迟，导致全血中血药浓度和钙调磷酸酶抑制之间的关系出现抗凝血滞后。与此相反，这种滞后回线减少后，重复给药的每种药物，和钙调磷酸酶活性的恢复率更大的抑制诱导的环孢素A比他克莫司。此外，他克莫司在较低的血液浓度下对全血中钙调磷酸酶活性的抑制作用与环孢菌素A相当。总体而言，效应室模型很好地描述了单次和重复给药后全血中钙调磷酸酶活性的时间曲线。这些结果表明，他克莫司和环孢素A对钙调磷酸酶的抑制作用不同。不同的药效学可能部分有助于接受钙调磷酸酶抑制剂的移植患者的治疗药物监测策略。
We have compared the pharmacodynamic properties of calcineurin inhibitors tacrolimus and cyclosporin A in rats to clarify the different therapeutic drug monitoring strategy of both drugs in a clinical situation. In various tissue extracts, the inhibition of calcineurin activity by cyclosporin A was significantly greater than that by tacrolimus at the same drug concentration ( 1 muM) in the thymus, heart, liver, spleen, kidney, and testis ( p < 0.05). The time profiles of blood concentrations and calcineurin activity in whole blood were examined after single or repeated administration of each drug in rats. A substantial time delay in the inhibition was observed following the single administration of tacrolimus or cyclosporin A, resulting in an anticlockwise hysteresis in the relationship between blood concentrations and calcineurin inhibition in whole blood. In contrast, such a hysteresis loop diminished after the repeated administration of each drug, and the recovery rate of calcineurin activity was greater for the inhibition induced by cyclosporin A than by tacrolimus. Furthermore, tacrolimus produced a comparable inhibition of calcineurin activity in whole blood at lower blood concentrations than cyclosporin A. Overall, the effect compartment model well described the time profiles of calcineurin activity in whole blood after the single and repeated administrations of each drug. These findings suggest that the properties of calcineurin inhibition differ between tacrolimus and cyclosporin A. Distinct pharmacodynamics may partly contribute to the therapeutic drug monitoring strategy in transplant patients receiving calcineurin inhibitors.