Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat

Purpose: The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used.

Methods: Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg-1 given i.v., i.p. and p.o.). Total plasma cholesterol levels increased from 0.82-2.02 to 5.27-11.05 mmol L-1 48 h post P407 administration (1 g kg-1, i.p.). Protein binding studies were conducted by an ultrafiltration method.

Results: Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and i.p. doses, respectively, thereby increasing AUC0-infinity, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0-infinity was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%.

Conclusions: The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.