Abstract

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.