Sugioka N, Koyama H, Kawakubo M, Ohta T, Kishimoto H, Mori S, Nakajima K
Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Japan.
J Pharm Pharmacol. 1996 Dec;48(12):1327-31. doi: 10.1111/j.2042-7158.1996.tb03944.x.
To determine whether the age-dependent increase in the pharmacological effect of calcium-channel blockers is a result of age-dependent alteration of the unbound fraction the drug in serum, the unbound fraction of the nicardipine was investigated in the serum of 38 adults. The unbound concentration of nicardipine in serum to which nicardipine (205.4 ng mL-1) had been added was determined by ultracentrifugation to range from 0.49 to 4.01% (mean +/- s.d., 1.55 +/- 0.78%). Non-glycosylated albumin was most strongly correlated with age (r = 0.901). Total bilirubin was weakly correlated with age whereas levels of alpha-1-acid glycoprotein, triglycerides and glycosylated albumin were not correlated with age. A significant (P < 0.01) linear correlation was obtained between the unbound fraction of nicardipine and parameters such as age, albumin, albumin/globulin ratio, albumin/glycosylated albumin ratio, non-glycosylated albumin and total bilirubin. To assess the relative effect of each variable on the unbound fraction of nicardipine, stepwise multiple linear regression was performed using age and biochemical parameters. The three variables (non-glycosylated albumin, total bilirubin and age) were entered into the regression equation. The results of this study showed that the major ligand of nicardipine in serum was non-glycosylated albumin, which decreased with age. It was, moreover, shown that the serum-unbound concentration of nicardipine increased with age. This finding would be one factor accounting for the increase in the pharmacological effect of nicardipine with age. In addition, our predicted model for the unbound fraction of nicardipine might be useful in determining the appropriate nicardipine dose for the elderly.
为了确定钙通道阻滞剂药理作用随年龄增长而增强是否是由于血清中药物游离分数随年龄发生改变，研究了38名成年人血清中尼卡地平的游离分数。通过超速离心法测定加入尼卡地平（205.4 ng/mL）后的血清中尼卡地平的游离浓度，范围为0.49%至4.01%（平均值±标准差，1.55±0.78%）。非糖基化白蛋白与年龄的相关性最强（r = 0.901）。总胆红素与年龄呈弱相关，而α-1-酸性糖蛋白、甘油三酯和糖基化白蛋白水平与年龄无关。尼卡地平的游离分数与年龄、白蛋白、白蛋白/球蛋白比值、白蛋白/糖基化白蛋白比值、非糖基化白蛋白和总胆红素等参数之间存在显著（P < 0.01）线性相关。为了评估每个变量对尼卡地平游离分数的相对影响，使用年龄和生化参数进行逐步多元线性回归。将三个变量（非糖基化白蛋白、总胆红素和年龄）纳入回归方程。本研究结果表明，血清中尼卡地平的主要配体是非糖基化白蛋白，其随年龄降低。此外，还表明尼卡地平的血清游离浓度随年龄增加。这一发现可能是尼卡地平药理作用随年龄增加的一个因素。此外，我们预测的尼卡地平游离分数模型可能有助于确定老年人合适的尼卡地平剂量。
