Finn W F, McCormack A J, Sullivan B A, Hak L J, Clark R L
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill 27599.
Ren Fail. 1989;11(1):3-15. doi: 10.3109/08860228909066940.
The effect of the rate of infusion of single and multiple doses of cyclosporine (CsA) on renal function was evaluated in Sprague-Dawley rats. CsA was dissolved in cremophore (Crem) or Tween 80 (Tween) and infused over consecutive 10-min periods at doses of 10, 20, 30 and 40 mg/kg. CsA-Crem and CsA-Tween produced similar and progressive changes in MAP, RBF, and RVR. By the end of the infusion, the mean values (% of control) of MAP (122 +/- 16% and 131 +/- 22%), RBF (56 +/- 11% and 66 +/- 20%), and RVR (222 +/- 38% and 232 +/- 134%) were significantly different from their respective preinfusion values. Infusion of Crem alone resulted in renal vasodilation at low doses and renal vasoconstriction at high doses. Vasoconstriction was not produced by infusion of Tween alone. In addition, animals were treated with vehicle alone (Gp 1), CsA 10 mg/kg/day by injection (Gp 2), or CsA 20 mg/kg/day by i.v. infusion over 4 hr (Gp 3), and were studied at 1 week. Systemic toxicity was greater with the 4-hr infusion as judged by an increase in MAP. The mean values of MAP were 107 +/- 8 (Gp 1), 101 +/- 13 (Gp 2), and 135 +/- 5 mm Hg (Gp 3; p less than 0.05). However, renal function was less severely affected with the 4-hr infusion. The mean values of CIn were 434 +/- 99 (Gp 1), 298 +/- 101 (Gp 2; p less than 0.05), and 425 +/- 114 microL/min/100 g BW (Gp 3); and the mean values for RBF were 2.72 +/- 0.74 (Gp 1), 2.08 +/- 0.17 (Gp 2; p less than 0.05), and 3.35 +/- 0.61 mL/min/100 g BW (Gp 3), respectively. Microangiograms showed marked abnormalities in the intrarenal perfusion pattern in the rats injected with CsA, 10 mg/kg BW. In rats infused over 4 hr with CsA, 20 mg/kg BW, the microangiographic pattern was normal. These studies demonstrate that the acute hemodynamic effects of CsA are directly related to the rate of infusion. Furthermore, the renal toxicity which follows repetitive injection of CsA can be minimized or avoided by administering CsA as a slow infusion. In addition to the total dose administered, the rate of infusion is an important determinant of nephrotoxicity.
在斯普拉格-道利大鼠中评估了单剂量和多剂量环孢素（CsA）输注速率对肾功能的影响。CsA溶解于聚氧乙烯蓖麻油（Crem）或吐温80（Tween）中，以10、20、30和40mg/kg的剂量在连续10分钟内输注。CsA-Crem和CsA-Tween在平均动脉压（MAP）、肾血流量（RBF）和肾血管阻力（RVR）方面产生了相似且渐进性的变化。输注结束时，MAP（122±16%和131±22%）、RBF（56±11%和66±20%）以及RVR（222±38%和232±134%）的平均值（相对于对照组的百分比）与其各自的输注前值相比有显著差异。单独输注Crem在低剂量时导致肾血管舒张，在高剂量时导致肾血管收缩。单独输注Tween不会产生血管收缩。此外，动物分别接受单独的赋形剂处理（第1组）、通过注射给予10mg/kg/天的CsA（第2组）或通过静脉输注4小时给予20mg/kg/天的CsA（第3组），并在1周时进行研究。通过MAP的升高判断，4小时输注的全身毒性更大。MAP的平均值分别为107±8（第1组）、101±13（第2组）和135±5mmHg（第3组；p<0.05）。然而，4小时输注对肾功能的影响较小。肌酐清除率（CIn）的平均值分别为434±99（第1组）、298±101（第2组；p<0.05）和425±114μL/min/100g体重（第3组）；RBF的平均值分别为2.72±0.74（第1组）、2.08±0.17（第2组；p<0.05）和3.35±0.61mL/min/100g体重（第3组）。微血管造影显示，注射10mg/kg体重CsA的大鼠肾内灌注模式有明显异常。在4小时内输注20mg/kg体重CsA的大鼠中，微血管造影模式正常。这些研究表明，CsA的急性血流动力学效应与输注速率直接相关。此外，通过缓慢输注CsA可将重复注射CsA后的肾毒性降至最低或避免。除了给药的总剂量外，输注速率也是肾毒性的一个重要决定因素。
