尼莫地平：脑缺血患者的药物药代动力学及血浆腺苷水平

Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia.

作者信息

Blardi Patrizia, Urso Renato, De Lalla Arianna, Volpi Luciana, Perri Tullio Di, Auteri Alberto

机构信息

Center of Clinical Pharmacology, Department of Internal Medicine, University of Siena, Italy.

出版信息

Clin Pharmacol Ther. 2002 Nov;72(5):556-61. doi: 10.1067/mcp.2002.128127.

DOI:10.1067/mcp.2002.128127

PMID:12426519

Abstract

BACKGROUND AND OBJECTIVE

Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia.

METHODS

Twelve patients with cerebral ischemia (9 men and 3 women; mean age, 68.8 +/- 11.2 years; mean weight, 67.9 +/- 9.3 kg) were admitted to the study. They received nimodipine intravenously (a bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during different sessions. Blood samples for adenosine and nimodipine were collected at fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were detected by HPLC methods.

RESULTS

Both the intravenous and oral administrations induced a statistically significant increase in plasma adenosine levels (P <.001), which appeared to be related to the dose and route of drug administration. In particular, a 67.8% increase was observed after intravenous administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30 mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters of nimodipine after intravenous administration were as follows: peak concentration (C(max)), 319.6 +/- 38.9 ng/mL at the first sampling time; area under the curve (AUC), 239 +/- 25 ng. h/mL; and terminal half-life, 3.12 +/- 0.97 hours. After oral administration, the drug kinetics was linear in the administered dose range and the pharmacokinetic parameters were as follows: C(max)(30 mg), 46.1 +/- 5.8 ng/mL; C(max)(60 mg), 81.7 +/- 14.6 ng/mL; C(max)(90 mg), 131.6 +/- 16.3 ng/mL; AUC(30 mg), 119 +/- 25 ng. h/mL; AUC(60 mg), 256 +/- 48 ng. h/mL; and AUC(90 mg), 389 +/- 54 ng. h/mL. The half-life was similar to the values observed after intravenous administration, whereas the bioavailability ranged between 2% and 5.9%.

CONCLUSIONS

Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.

摘要

背景与目的

尼莫地平是一种二氢吡啶类钙通道阻滞剂，用于治疗蛛网膜下腔出血的缺血性损伤。最近的研究表明，它能够抑制人红细胞和顶叶皮质神经元中的腺苷转运。在本研究中，我们调查了尼莫地平的药代动力学及其对脑缺血患者血浆腺苷水平的影响。

方法

12例脑缺血患者（9例男性，3例女性；平均年龄68.8±11.2岁；平均体重67.9±9.3kg）纳入本研究。他们在不同时间段接受静脉注射尼莫地平（0.03mg/kg推注）和口服尼莫地平（单次剂量30mg、60mg和90mg）。在长达480分钟的固定时间间隔采集血样检测腺苷和尼莫地平。采用高效液相色谱法检测腺苷和尼莫地平的血浆水平。

结果

静脉注射和口服给药均导致血浆腺苷水平出现统计学显著升高（P<.001），这似乎与给药剂量和途径有关。具体而言，静脉注射后观察到升高67.8%，分别给予30mg、60mg和90mg尼莫地平后，观察到升高28.9%、43.6%和60.2%。静脉注射后尼莫地平的药代动力学参数如下：首次采样时的峰浓度（C(max)）为319.6±38.9ng/mL；曲线下面积（AUC）为239±25ng·h/mL；终末半衰期为3.12±0.97小时。口服给药后，在所给剂量范围内药物动力学呈线性，药代动力学参数如下：C(max)(30mg)为46.1±5.8ng/mL；C(max)(60mg)为81.7±14.6ng/mL；C(max)(90mg)为131.6±16.3ng/mL；AUC(30mg)为119±25ng·h/mL；AUC(60mg)为256±48ng·h/mL；AUC(90mg)为389±54ng·h/mL。半衰期与静脉注射后观察到的值相似，而生物利用度在2%至5.9%之间。