Eliot L A, Jamali F
University of Alberta, Edmonton, Alberta, Canada.
J Pharmacol Exp Ther. 1999 Oct;291(1):188-93.
Nifedipine, a hypertensive calcium channel blocker, is commonly administered to subjects with coronary heart disease who often exhibit hyperlipidemia. In general, the pharmacokinetic consequences of hyperlipidemia include increased total drug concentrations and decreased unbound fraction in plasma. However, the pharmacodynamic consequences of hyperlipidemia are conflicting; unaltered, increased, or decreased pharmacological effects are reported. In this study, the effect of experimental hyperlipidemia on pharmacokinetic and pharmacodynamic consequences of nifedipine was studied. After establishing a dose (0.05-0.3 mg.kg(-1))-effect relationship, single 0.1 mg.kg(-1) i.v. doses of nifedipine were administered to control and poloxamer 407-induced hyperlipidemic (with and without cholesterol-lowering agent atorvastatin) rats. Mean arterial pressure, total as well as unbound nifedipine plasma concentrations, and total cholesterol were monitored. Hyperlipidemia significantly decreased systemic clearance of nifedipine by 40% and increased T(1/2) and area under the plasma concentration-time curve by 85 and 65%, respectively. Compared with the hyperlipidemic group, atorvastatin-treated rats had significantly lower total plasma cholesterol (0-70%), increased systemic clearance (39%), and decreased T(1/2) (27%) and area under the plasma concentration-time curve (24%). Hyperlipidemia prolonged pharmacological T(1/2) of nifedipine by 300%. Atorvastatin treatment significantly reduced this prolongation to 46%. There was a significant correlation between mean blood pressure and the total but not unbound nifedipine plasma concentrations. Hyperlipidemia potentiates the hypotensive effect of nifedipine by increasing its total plasma concentrations despite decreased unbound drug concentration.
硝苯地平是一种用于治疗高血压的钙通道阻滞剂，常用于患有冠心病且常伴有高脂血症的患者。一般来说，高脂血症对药物代谢动力学的影响包括总药物浓度升高和血浆中游离药物分数降低。然而，高脂血症对药效学的影响却存在矛盾；有报道称其药理作用未改变、增强或减弱。在本研究中，研究了实验性高脂血症对硝苯地平药代动力学和药效学的影响。在建立剂量（0.05 - 0.3 mg·kg⁻¹）-效应关系后，对对照组和泊洛沙姆407诱导的高脂血症大鼠（分别给予和未给予降胆固醇药物阿托伐他汀）静脉注射单次剂量为0.1 mg·kg⁻¹的硝苯地平。监测平均动脉压、硝苯地平的总血浆浓度和游离血浆浓度以及总胆固醇。高脂血症使硝苯地平的全身清除率显著降低40%，使半衰期（T₁/₂）和血浆浓度-时间曲线下面积分别增加85%和65%。与高脂血症组相比，阿托伐他汀治疗的大鼠总血浆胆固醇显著降低（0 - 70%），全身清除率增加（39%），半衰期（T₁/₂）和血浆浓度-时间曲线下面积降低（分别为27%和24%）。高脂血症使硝苯地平的药理半衰期延长了300%。阿托伐他汀治疗显著将这种延长降低至46%。平均血压与硝苯地平的总血浆浓度之间存在显著相关性，但与游离血浆浓度无关。尽管游离药物浓度降低，但高脂血症通过增加硝苯地平的总血浆浓度增强了其降压作用。
