硝苯地平骨架型缓释微丸在大鼠体内药代动力学及其与CYP3A4代谢酶活性的关系
Pharmacokinetics of nifedipine matrix sustained-release pellets in rats and the relationship with CYP3A4
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摘要: 考察自制硝苯地平骨架型缓释微丸在大鼠体内药代动力学行为，并研究其与CYP3A4代谢酶活性的关系。首先建立用于CYP3A4活性测定的梯度洗脱高效液相色谱法，同时测定大鼠尿中的6β-羟基氢化可的松(6β-OHF)和氢化可的松(FC)含量；以尿液中6β-OHF和FC之比作为活性指标。以FC为探针，测定10只大鼠体内的CYP3A4酶活性；然后建立硝苯地平大鼠体内的分析测定方法，以市售硝苯地平片为参比制剂进行大鼠体内药物动力学研究；同时研究CYP3A4酶活性与硝苯地平大鼠体内药代动力学性质的关系。研究结果显示，10只大鼠CYP3A4酶活性为0.271±0.129；自制硝苯地平骨架型缓释微丸cmax显著降低约70%，tmax显著增加约400%、t1/2和MRT增加约230%，AUC0-∞无显著差异。硝苯地平缓释微丸与市售制剂相比，在大鼠体内具有明显的缓释效果，且CYP3A4酶活性会影响其药代动力学行为。Abstract: To conduct the characterization of its pharmacokinetics in rats of nifedipine sustained-release pellets and to study the relationship between the pellets and CYP3A4 activity. A gradient HPLC method was developed to simultaneously determine 6β-hydroxycortisol and hydrocortisone. CYP3A4 activity of rats was quantified by urinary ratio of 6β-hydroxycortisol/hydrocortisone after intravenous injection of hydrocortisone as a biomarker. HPLC method was also developed to quantify the drug concentration in plasma of rats, and the studies of pharmacokinetics were performed after oral administration of single dose of two formulations: Nifedipine matrix sustained-release pellets and nifedipine tablet(using as control). The results showed that the ratio of ten rats was 0. 271±0. 129. cmax of nifedipine sustained-release pellets decreases by nearly 70%, tmax significantly increased by 400% and t1/2 and MRT significantly increased by 230% compared to control. Nifedipine sustained-release pellets had a significant sustained-release property compared to the control and CYP3A4 activity affected its pharmacokinetics behavior.
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Keywords:
- nifedipine /
- sustained-release pellets /
- pharmacobinetics /
- CYP3A4 /
- 6β-hydroxycortisol /
- hydrocortisone
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