Pharmacokinetics and pharmacodynamics of nifedipine in untreated and atorvastatin-treated hyperlipidemic rats

Nifedipine, a hypertensive calcium channel blocker, is commonly administere d to subjects with coronary heart disease who often exhibit hyperlipidemia. In general, the pharmacokinetic consequences of hyperlipidemia include inc reased 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 establis hing 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-ind uced hyperlipidemic (with and without cholesterol-lowering agent atorvastat in) rats. Mean arterial pressure, total as well as unbound nifedipine plasm a concentrations, and total cholesterol were monitored. Hyperlipidemia sign ificantly decreased systemic clearance of nifedipine by 40% and increased T -1/2 and area under the plasma concentration-time curve by 85 and 65%, resp ectively. Compared with the hyperlipidemic group, atorvastatin-treated rats had significantly lower total plasma cholesterol (0-70%), increased system ic clearance (39%), and decreased T-1/2 (27%) and area under the plasma con centration-time curve (24%). Hyperlipidemia prolonged pharmacological T-1/2 of nifedipine by 300%. Atorvastatin treatment significantly reduced this p rolongation to 46%. There was a significant correlation between mean blood pressure and the total but not unbound nifedipine plasma concentrations. Hy perlipidemia potentiates the hypotensive effect of nifedipine by increasing its total plasma concentrations despite decreased unbound drug concentrati on.