Brown Morris J, Toal Corey B
University of Cambridge, Clinical Pharmacology Unit, Addenbrookes Hospital, Cambridge, UK.
Br J Clin Pharmacol. 2008 May;65(5):646-52. doi: 10.1111/j.1365-2125.2007.03082.x. Epub 2007 Dec 17.
Pharmacokinetic and pharmacodynamics studies are usually carried out separately with theoretical linking or interpretations. The pharmacokinetics of short- vs. long-acting formulations of nifedipine is well known, but the pharmacokinetics of different once-a-day formulations of nifedipine is generally not well known by the practising physician.
This study provides practical patient-based information linking pharmacokinetics to pharmacodynamics in one of the target populations of patients, those with hypertension, who might receive the two different drugs. AIMS The haemodynamic responses to nifedipine vary between short- and long-acting formulations. However, the latter have not been compared despite marked differences in their constitution. Our 1-month randomized, crossover study was designed to compare the 30-mg osmotic, constant-release nifedipine gastrointestinal therapeutic system (N-GITS) with an encapsulated mini-tablet Coracten XL.
Forty-four hypertensive patients aged 63 +/- 7 years were studied. The formulation was changed on day 15 and (for a single dose) day 30. At days 0, 14, 15, 29 and 30, patients were monitored for 6 h after dosing, during which blood pressure (BP), heart rate (HR) and plasma levels of norepinephrine (NE) and nifedipine were measured. The primary outcome was the difference in plasma NE between formulations at the time of peak nifedipine level.
Systolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 +/- 8.8 beats min(-1). After N-GITS HR fell by 2.4 +/- 7.7 beats min(-1) (P = 0.159). Plasma NE was higher in the Coracten- (480 +/- 38.3 pg ml(-1)) than N-GITS-treated patients (343 +/- 75.0 pg ml(-1)) at the time of peak nifedipine concentrations (4 and 5 h, respectively) and their change from baseline was significantly (P = 0.0046) different. A similar difference between the drugs was seen again at days 15 and 30, at 5 h after switching formulations.
This study suggests that two different formulations of once-daily nifedipine result in different BP and plasma NE responses, and that switching between formulations causes opposite effects upon the sympathetic nervous response to falling BP.
药代动力学和药效学研究通常是分别进行的，仅通过理论联系或解释。硝苯地平短效与长效制剂的药代动力学已为人熟知，但硝苯地平不同一日一次剂型的药代动力学对于执业医师而言通常并不十分清楚。
本研究为目标患者群体之一（即可能接受这两种不同药物的高血压患者）提供了基于患者的实用信息，将药代动力学与药效学联系起来。
硝苯地平的血流动力学反应在短效和长效制剂之间有所不同。然而，尽管它们的组成存在显著差异，但后者尚未进行比较。我们为期1个月的随机交叉研究旨在比较30毫克渗透型控释硝苯地平胃肠道治疗系统（N-GITS）与一种胶囊型迷你片可力洛XL。
对44名年龄为63±7岁的高血压患者进行了研究。在第15天和（单次给药时）第30天更换剂型。在第0、14、15、29和30天，给药后对患者进行6小时监测，在此期间测量血压（BP）、心率（HR）以及去甲肾上腺素（NE）和硝苯地平的血浆水平。主要结局是硝苯地平血药浓度峰值时不同剂型之间血浆NE的差异。
服用可力洛的首剂后收缩压迅速下降，在5小时达到最低点。心率上升1.2±8.8次/分钟。服用N-GITS后心率下降2.4±7.7次/分钟（P = 0.159）。在硝苯地平浓度峰值时（分别为4小时和5小时），可力洛治疗组患者的血浆NE（480±38.3皮克/毫升）高于N-GITS治疗组患者（343±75.0皮克/毫升），且它们相对于基线的变化有显著差异（P = 0.0046）。在第15天和第30天更换剂型后5小时，两种药物之间再次出现类似差异。
本研究表明，两种不同的一日一次硝苯地平剂型会导致不同的血压和血浆NE反应变化，并且剂型转换会对血压下降时的交感神经反应产生相反的影响。
