Marques Maria Paula, Coelho Eduardo Barbosa, Dos Santos Neife Aparecida Guinaim, Geleilete Tufik José Magalhães, Lanchote Vera Lucia
Faculdade de Ciências Farmacêuticas, Universidade São Paulo, Brazil.
Eur J Clin Pharmacol. 2002 Dec;58(9):607-14. doi: 10.1007/s00228-002-0528-4. Epub 2002 Nov 16.
Nisoldipine (N) is a dihydropyridine calcium antagonist marketed as a racemic mixture and used for the treatment of hypertension. In the present study, we investigated the influence of type-2 diabetes mellitus (DM) on the enantioselective pharmacokinetic and dynamic parameters of N.
Seventeen hypertensive patients, nine of them with DM, were investigated in a cross-over study with administration of rac-N as coat-core tablets (20 mg day(-1)) or placebo for 15 days each. Serial blood samples (0-24 h) were collected on the 15th day, and 24-h ambulatory blood pressure (BP) monitoring was simultaneously evaluated. N enantiomers in plasma samples were analysed using chiral high-performance liquid chromatography combined with gas chromatography/mass spectrometry. The enantiomeric ratios differing from one were evaluated using the Wilcoxon test, and the results are reported as means with the 95% confidence intervals. A lidocaine (L) test was carried out as an in vivo marker of CYP3A4 (and CYP1A2) activities.
The following differences were observed between the (+)-N and (-)-N enantiomers, respectively, in the patients presenting with DM (means and ranges): C(max) 3.9 (1.7-6.1) ng ml(-1) versus 0.7 (0.4-1.0) ng ml(-1), AUC(0-24) 51.5 (29.0-74.0) ng ml(-1) h versus 9.4 (5.9-12.8) ng ml(-1) h, and Cl/f 3.6 (1.9-5.4) l h(-1) kg(-1) versus 18.7 (11.7-25.7) l h(-1) kg(-1). The Cl/f value of (+)-N was lower (Mann-Whitney test) in patients with DM: 6.0 (4.3-7.5) l h(-1) kg(-1) versus 3.6 (1.9-5.4) l h(-1) kg(-1). The same observation was made for the (-)-N, with Cl/f reaching 38.8 (26.8-51.0) l h(-1) kg(-1) and 18.7 (11.7-25.7) l h(-1) kg(-1) for the non-diabetic and DM groups, respectively. The L test resulted in higher ratios (P < 0.05) of plasma L/MEGX concentrations (30 min after i.v. L) for DM (11.1 vs 18.6). N significantly reduced systolic and diastolic BP (P < 0.05, Wilcoxon test) in all patients investigated relative to placebo. No differences in BP reduction were observed between diabetic and non-diabetic patients. N significantly increased noradrenaline concentrations in plasma of both patient groups. The data also demonstrated that the plasma concentrations of noradrenaline 30 min after N administration were lower (P < 0.05) in diabetic (mean 2.86 pmol ml(-1)) than in non-diabetic patients (4.80 pmol ml(-1)).
The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.
尼索地平（N）是一种作为外消旋混合物上市的二氢吡啶类钙拮抗剂，用于治疗高血压。在本研究中，我们调查了2型糖尿病（DM）对N对映体选择性药代动力学和动力学参数的影响。
17例高血压患者，其中9例患有DM，参与一项交叉研究，分别给予消旋N包芯片（20mg/天）或安慰剂，各持续15天。在第15天采集系列血样（0 - 24小时），并同时评估24小时动态血压（BP）监测情况。血浆样本中的N对映体采用手性高效液相色谱结合气相色谱/质谱法进行分析。使用Wilcoxon检验评估与1不同的对映体比率，结果以均值和95%置信区间报告。进行利多卡因（L）试验作为CYP3A4（和CYP1A2）活性的体内标志物。
在患有DM的患者中，分别观察到（+）-N和（-）-N对映体之间存在以下差异（均值和范围）：C(max) 3.9（1.7 - 6.1）ng/ml对0.7（0.4 - 1.0）ng/ml，AUC(0 - 24) 51.5（29.0 - 74.0）ng/ml·h对9.4（5.9 - 12.8）ng/ml·h，以及Cl/f 3.6（1.9 - 5.4）l/h·kg对18.7（11.7 - 25.7）l/h·kg。DM患者中（+）-N的Cl/f值较低（Mann - Whitney检验）：6.0（4.3 - 7.5）l/h·kg对3.6（1.9 - 5.4）l/h·kg。（-）-N也有相同发现，非糖尿病组和DM组的Cl/f分别达到38.8（26.8 - 51.0）l/h·kg和18.7（11.7 - 25.7）l/h·kg。L试验导致DM患者血浆L/MEGX浓度（静脉注射L后30分钟）的比率更高（P < 0.05）（11.1对18.6）。相对于安慰剂，N使所有研究患者的收缩压和舒张压显著降低（P < 0.05，Wilcoxon检验）。糖尿病患者和非糖尿病患者之间在血压降低方面未观察到差异。N使两组患者血浆去甲肾上腺素浓度显著升高。数据还表明，DM患者在给予N后30分钟血浆去甲肾上腺素浓度低于非糖尿病患者（P < 0.05）（均值2.86 pmol/ml对4.80 pmol/ml）。
目前的数据使我们能够推断，2型糖尿病改变了（+）-N优映体和（-）-N劣映体的动力学处置，推测是由于CYP3A4活性较低，尽管它并未改变血压降低所带来的临床效果。
