Eliot L A, Foster R T, Jamali F
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Pharm Res. 1999 Feb;16(2):309-13. doi: 10.1023/a:1018896912889.
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.
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.
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%.
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.
研究高脂血症对硝苯地平药代动力学的影响。高脂血症影响药物药代动力学的机制主要尚未明确。高脂血症可能会降低血浆中游离药物的比例和/或由于膜胆固醇过多而降低细胞色素P - 450系统的内在能力。高脂血症是导致高血压和缺血性心脏病的冠状动脉疾病的主要危险因素，而硝苯地平作为一种钙通道阻滞剂可用于治疗这些疾病。
采用泊洛沙姆407（P407）诱导的高脂血症大鼠模型，研究高脂血症对硝苯地平（静脉注射、腹腔注射和口服给药，剂量均为6 mg·kg⁻¹）药代动力学的影响。腹腔注射P407（1 g·kg⁻¹）48小时后，总血浆胆固醇水平从0.82 - 2.02 mmol·L⁻¹升高至5.27 - 11.05 mmol·L⁻¹。通过超滤法进行蛋白结合研究。
高脂血症使口服和腹腔注射给药后CLTB分别显著降低38%，CLTB/F分别显著降低45%和42%，从而增加了AUC0 - ∞、Cmax和半衰期。绝对生物利用度和Vdss保持不变。AUC0 - ∞在每种给药途径中受到的影响程度相同，因此，这种影响主要是全身性的而非首过效应。高脂血症使血浆中游离药物比例显著降低约31%。
P407诱导的高脂血症导致硝苯地平药代动力学改变，至少部分原因可能是血浆中游离药物比例降低。然而，不能排除内在清除率降低的可能性。
