Zhou Ying, He Xiao-Meng, Li Hu-Qun, Ni Yang, Xu Ming-Zhen, Chen Hui, Li Wei-Yong
Institute of Clinic Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
J Huazhong Univ Sci Technolog Med Sci. 2014 Dec;34(6):856-860. doi: 10.1007/s11596-014-1364-3. Epub 2014 Dec 6.
The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentration of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the highest concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite rapidly.
本研究的目的是分别考察超短效钙拮抗剂克利夫地平在比格犬和斯普拉格-道利大鼠体内的药代动力学特征及组织分布情况。同时还评估了其主要代谢产物H152/81的药代动力学和生物分布。犬以17 μg/(kg·min)的剂量速率静脉输注克利夫地平，大鼠静脉注射5 mg/kg的克利夫地平。采集犬血浆和大鼠组织，采用高效液相色谱-串联质谱法进行测定。结果发现，血浆中克利夫地平迅速达到稳态浓度。终末半衰期较短（16.8分钟），表明输注结束后清除迅速。总清除率为5 mL/(min·kg)。相比之下，H152/81的血浆浓度上升较慢，且显著高于克利夫地平。静脉给药后，克利夫地平迅速分布到所有检测的组织中，在脑、心脏和肝脏中浓度最高。给药后10分钟，大多数组织中克利夫地平的浓度达到最大值。然而，与总给药剂量相比，克利夫地平在所有组织中的分布比例相当小（0.042‰）。提示克利夫地平主要分布在血液中，并迅速转化为无活性的代谢产物。
