载异烟肼、利福平白蛋白纳米粒中异烟肼在兔腰椎及其椎旁肌组织分布及药代动力学研究

Pharmacokinetics and tissue distribution of isoniazid released from albumin nanoparticles loaded with isoniazid and rifampicin in rabbit spine

中文关键词:  纳米粒  异烟肼  脊柱  椎旁肌  反相高效液相色谱法  药代动力学

英文关键词:Nanoparticle  Isoniazid  Spine  Paravertebral muscle  RP-HPLC  Pharmacokinetics

中文摘要:

  【摘要】 目的：研究载异烟肼、利福平白蛋白纳米粒（INH-RFP-BSA-NPs）经静脉给药后异烟肼（isoniazid，INH）在兔腰椎及其椎旁肌中的生物分布及药代动力学特性。方法：选取132只健康成年新西兰大白兔，平均分为两组，以普通异烟肼制剂作为对照，经兔耳缘静脉分别注射INH-RFP-BSA-NPs溶液与异烟肼注射液。采用反相高效液相色谱（RP-HPLC）分析方法，检测各时间点（1、2、4、8、12、24、36、48、72、96、120h）兔L6椎体和椎旁肌组织中异烟肼的药物浓度。使用DAS 3.2.1软件计算各组织中异烟肼的药物浓度-时间曲线下面积（AUC）、半衰期（t1/2）、平均驻留时间（MRT）等主要药代动力学参数。根据纳米制剂与异烟肼普通制剂在各时间点靶器官组织药物浓度及药时曲线下面积的比值，计算靶向指数（DTI）及相对靶向效率（RTE），评价INH-RFP-BSA-NPs对兔脊柱及椎旁肌的靶向性。结果：各时间点实验组兔L6椎体及椎旁肌组织中异烟肼浓度均高于对照组。药代动力学结果显示：实验组兔椎体中AUC0→∞为（533.71±162.44）μg/g·h，t1/2为（55.32±38.38）h，MRT为（58.12±44.26）h；椎旁肌中AUC0→∞为（17.40±4.89）μg/g·h，t1/2为（25.78±6.05）h，MRT为（27.77±8.51）h。对照组兔椎体中AUC0→∞为（278.61±41.90）μg/g·h，t1/2为（14.90±7.10）h，MRT为（18.92±6.11）h；椎旁肌中AUC0→∞为（7.38±0.93）μg/g·h，t1/2为（5.97±2.68）h，MRT为（5.20±0.8）h。相对于对照组，实验组兔椎体和椎旁肌组织中AUC值显著增高（P＜0.01），MRT、t1/2延长（P＜0.05或P＜0.01）。兔椎体及椎旁肌中的DTI、RTE值基本都大于1。结论：与异烟肼普通制剂相比，INH-RFP-BSA-NPs使异烟肼在兔腰椎及其椎旁肌组织中浓度升高、消除减慢，具有良好的药代动力学特征，明显提高了异烟肼在兔腰椎及其椎旁肌的药物分布。

英文摘要:

  【Abstract】 Objectives: To study the pharmacokinetics and tissue distribution of isoniazid(INH) released from albumin nanoparticles loaded with isoniazid and rifampicin(INH-RFP-BSA-NPs) in rabbit′s spine and paravertebral muscles after intravenous administration. Methods: 132 healthy New Zealand white rabbits were averagely divided into 2 groups at random. The regular dosage formed INH preparations as control. Then tissue samples were obtained at certain time points(1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120h). The pharmacokinetics were tested after injection of INH-RFP-BSA-NPs and INH solution via the rabbit′s ear vein. Drug concentration of INH in vertebral and paravertebral muscle tissues was detected by reversed-phase high-performance liquid chromatography(RP-HPLC) method at each time point. The main parameters of pharmacokinetics, including area under concentration-time curve(AUC), half life period(t1/2) and the mean residence time(MRT) were calculated by DAS 3.2.1. Drug targeting index(DTI) and relative targeting efficiency (RTE) were applied to assess the targeting ability of INH-RFP-BSA-NPs. Results: At each time point, INH concentration in the experimental group was slightly higher than that in control group. Pharmacokinetic results of experimental group were AUC0→∞ as (533.71±162.44)μg/g·h, t1/2 as (55.32±38.38)h, MRT as (58.12±44.26)h in rabbit′s spine; AUC0→∞ as (17.40±4.89)μg/g·h, t1/2 as (25.78±6.05)h, MRT as (27.77±8.51)h in rabbit′s paravertebral muscles. Those of control group were AUC0→∞ as (278.61±41.90)μg/g·h, t1/2 as (14.90±7.10)h, MRT as (18.92±6.11)h in rabbit′s spine. In rabbit′s paravertebral muscles, AUC0→∞ was (7.380.93)μg/g·h, t1/2 was (5.97±2.68)h, MRT was (5.20±0.8)h. Compared with INH solution, its AUC was significantly higher(P＜0.01) after intravenous injection of INH-RFP-BSA-NPs, MRT and t1/2 were prolonged(P＜0.05 or P＜0.01). RTE and DTI were greater than one. Conclusions: Comparing to the general formulation of INH, INH-RFP-BSA-NPs can effectively improve the pharmacokinetics behaviour and have more prolonged release effect in rabbit′s spine.