目的:观察皮下注射尼莫地平和口服尼莫地平在健康兔和蛛网膜下腔充血(SAH)兔体内的生物利用度,并探讨皮下给药是否优于口服给药并达到目标血清浓度。方法:采用随机数字表法将成年雄性NZW兔36只分为6组(n=6):口服尼莫地平组(5、15 mg/kg组),皮下注射尼莫地平组(2.5、5、15 mg/kg组),SAH+皮下注射尼莫地平组(2.5 mg/kg),测量各组尼莫地平的血浆浓度并进行统计学分析。结果:(1)口服15 mg/kg的尼莫地平会产生更高的峰值血浆浓度(Tmax),并且增加峰值血浆浓度(Cmax),曲线下面积(AUC)亦大于5 mg/kg。对于皮下给药后观察到达到Tmax的时间具有相反的趋势,其中15 mg/kg导致较低的Tmax,并且具有比5 mg/kg更低的AUC倾向。(2)相比口服给药,皮下注射组的平均尼莫地平浓度显著大于7 ng/mL(P <0.01),且尼莫地平血浆浓度保持在7 ng/ml以上的时间明显大于口服给药(P<0.01)。(3)健康NZW兔中2.5 mg/kg皮下尼莫地平产生的Cmax、Tmax和AUC值,与5和15 mg/kg皮下注射后测量值无显著性差异(P>0.05)。在24 h测量的平均尼莫地平浓度高于7 ng/mL的目标治疗水平条件下,健康NZW兔(12.9±10.0)ng/mL和SAH(11.8±4.6)ng/mL兔差异亦无统计学意义(P> 0.05)。结论:皮下施用尼莫地平优于口服尼莫地平,并可以将24 h后尼莫地平血浆水平维持在7 ng/mL以上,有助于研究尼莫地平治疗SAH后延迟血管痉挛的机制。
Objective: To observe the bioavailability of subcutaneous injection of nimodipine and oral administration of nimodipine in healthy rabbits and SAH rabbits, and determine whether subcutaneous administration is superior to oral administration and to target serum concentration.Methods:36 adult male NZW rabbits were divided into 6 groups (n=6) by random number table method:oral nimodipine group (5 mg/kg and 15 mg/kg), subcutaneous injection of nimodipine group (2.5 mg/kg, 5mg/kg,15 mg/kg), SAH+ subcutaneous injection of nimodipine group (2.5 mg/kg), plasma concentrations of nimodipine in each group were measured and statistical analysis was performed. Results: Oral administration of 15 mg/kg of nimodipine produced a higher Tmax and increased Cmax, which was also greater than 5 mg/kg. The time to peak plasma concentration (Tmax) observed after subcutaneous administration had an opposite trend, with 15 mg/kg resulting in a lower Tmax and a lower AUC tendency than 5 mg/kg. (2) Compared with oral administration, the average concentration of nimodipine in the subcutaneous group was significantly greater than 7 ng/mL (P<0.01), and the plasma concentration of nimodipine remained above 7 ng/mL for significantly longer than oral administration (P<0.01). (3) The Cmax, Tmax and AUC values of nimodipine in healthy NZW rabbits were not significantly different from those measured by subcutaneous injection of 5 and 15 mg / kg (P>0.05). There was no significant difference between healthy NZW rabbits (12.9±10.0) ng/mL and SAH (11.8±4.6) ng/mL NZW rabbits at the target level of treatment with an average nimodipine concentration of 7 ng/mL measured at 24 h (P>0.05). Conclusion: Subcutaneous administration of nimodipine is superior to oral nimodipine and can maintain the plasma level of nimodipine at 7 ng/mL after 24 h,which can help to study the mechanism of nimodipine in delaying vasospasm after SAH treatment.