Systemic toxicity of tacrolimus given by various routes and the response to dose reduction
Systemic toxicity of tacrolimus given by various routes and the response to dose reduction
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DOI：
10.1111/j.1442-9071.2005.00942.x
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发表时间：
2005-02-01
影响因子：
4
通讯作者：
Arici, G
中科院分区：
文献类型：
--
作者：
Akar, Y;Yucel, G;Arici, G
目的：评价他克莫司(FK-506)不同给药途径的长期全身毒性及减量对其毒性的影响。方法：实验动物为成年雌性Wistar大鼠120只，体重200~250g。将大鼠随机分为10组，每组12只，分别给予他克莫司滴入(0.3%)、玻璃体腔内注射(0.5 mg/kg体重/周)、肌肉注射(1 mg/kg体重/周)、小剂量静脉注射(1 mg/kg体重/周)和大剂量静脉注射(2 mg/kg体重/周)，共治疗3个月。对照组大鼠(每种给药途径各一只)用0.9%氯化钠溶液处理。在为期3个月的研究期间，每月测定他克莫司的血药浓度、全血细胞计数和生化指标。结果：对照组和实验组外用和玻璃体内注射他克莫司均未显示出任何全身毒性作用。低剂量组和高剂量组出现一定毒性反应(高血糖、高钾血症和肾毒性)的大鼠。他克莫司对减量反应良好，减量后低剂量组和高剂量组血糖浓度分别从247.4±42.3 mg/dL降至189.6±37.9 mg/dL(P<0.05)和237.4±41.1 mg/dL降至182.3±22.7 mg/dL(P<；0.05)。他克莫司治疗组大鼠。大剂量他克莫司后出现肝功能损害的大鼠对剂量减少没有反应。肌肉注射和低剂量和高剂量静脉注射的基线胆固醇浓度。他克莫司治疗组2个月末分别从87.4+/-14.0 mg/dL、86.4+/-14.0 mg/dL和90.4+/-14.3 mg/dL降至53.6+/-9.8 mg/dL、52.1+/-12.5 mg/dL和63.5+/-11.7 mg/dL。差异有统计学意义(P<；每个结果0.05)。结论：局部或玻璃体内给药似乎是系统安全的，而非肠道给药可引起一些全身性血液学变化，如剂量依赖的血清胆固醇浓度降低。减少剂量可能会预防这种不良反应。
Purpose: To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity.Methods: The study animals were 120 experimentally naive adult female Wistar rats weighing 200-250 g each. The rats were randomly divided into 10 equal groups (n = 12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/ week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period.Results: The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction, Following dose reduction, blood glucose concentrations decreased from 247.4 +/- 42.3 mg/dL to 189.6 +/- 37.9 mg/dL (P < 0.05), and from 237.4 +/- 41.1 mg/dL to 182.3 +/- 22.7 mg/dL (P < 0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 +/- 14.0 mg/dL, 86.4 +/- 14.0 mg/dL and 90.4 +/- 14.3 mg/dL to 53.6 +/- 9.8 mg/dL, 52.1 +/- 12.5 mg/dL and 63.5 +/- 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P < 0.05 for each result).Conclusion: Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects.