Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent
Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent
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DOI：
10.1007/s00280-007-0430-y
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发表时间：
2007-11-01
影响因子：
3
通讯作者：
Joshi, Harish C.
中科院分区：
文献类型：
--
作者：
Aneja, Ritu;Dhiman, Neerupma;Joshi, Harish C.
背景诺斯卡品是一种天然存在的止咳苯酞异喹啉生物碱，是一种微管蛋白结合剂，目前正处于I/II期临床试验中用于抗癌治疗。与现有的抗有丝分裂药如紫杉烷类和长春新碱不同，诺斯卡品是水溶性的，耐受性好，并且没有可检测到的毒性。方法采用蛋白酶水解法提取小鼠血浆中的诺斯卡品，采用高效液相色谱法（HPLC）测定诺斯卡品的含量，并研究其在小鼠体内的药代动力学。沉淀法，使用反相C8柱，移动的相由35%乙腈和65%乙酸铵缓冲液（pH 4.5）组成，在232 nm波长下检测。结果诺斯卡品在390 ~ 50，000 ng/ml范围内线性关系良好（定量下限为390 ng/ml），回收率接近80%。在10 mg/kg静脉给药后，小鼠在5 min时达到7.88 μ g/ml的平均血浆浓度，并在4 h时下降至不可检测水平。平均全身清除率为4.78 l/h。平均分布容积（V-d）为5.05 l。非房室分析得出那可丁的平均血浆浓度-时间曲线下面积（AUC）为53.42、64.08和198.35 μ g/ml，在t（max）为1.12、1.50、1.50和1.50时达到最大血浆浓度（C-max）为12.74、23.24和46.73 μ g/ml，结论建立了一种快速、简便的HPLC/UV法测定小鼠血浆中那可卡品的浓度，可用于肿瘤抑制剂量下那可卡品在小鼠体内的药代动力学研究。由于口服可用的抗癌药物是罕见的，因此，诺斯卡品，一种无害的药物，具有平均口服生物利用度为31.5%的研究剂量范围内值得进一步发展在人类的抗癌治疗。
Background Noscapine, a naturally occurring antitussive phthalideisoquinoline alkaloid, is a tubulin-binding agent currently in Phase I/II clinical trials for anticancer therapy. Unlike currently available antimitotics such as taxanes and vincas, noscapine is water-soluble, well tolerated, and shows no detectable toxicity.Objective The goal was to develop a simple, sensitive, quantitative, selective, and less time-consuming high-performance liquid chromatography (HPLC) method for determination of noscapine and to study its pharmacokinetics in mice models.Method Noscapine was extracted from mice plasma using the protein-precipitation method and detected using a reversed-phase C8 column with mobile phase consisting of 35% acetonitrile and 65% ammonium acetate buffer (pH 4.5) at 232 nm wavelength. Pharmacokinetic studies of noscapine were performed in mice following intravenous bolus at 10 mg/kg and oral administrations at 75, 150, and 300 mg/kg.Results The standard curves for noscapine estimation were linear between 390 and 50,000 ng/ml (lower limit of quantification was 390 ng/ml) and the recovery was similar to 80%. Following 10 mg/kg intravenous dose, mean plasma concentrations of 7.88 mu g/ml were achieved at 5 min in mice and declined with undetectable levels at 4 h. The mean total body clearance was 4.78 l/h. The mean volume of distribution (V-d) was 5.05 l. Non-compartmental analysis yielded the mean area under the plasma concentration-time curve (AUC) for noscapine as 53.42, 64.08, and 198.35 h mu g/ml reaching maximum plasma concentrations (C-max) of 12.74, 23.24, and 46.73 mu g/ml at a t(max) of 1.12, 1.50, and 0.46 h at the linearly increasing dose levels.Conclusion A rapid and simple HPLC/UV method for the quantification of noscapine in plasma has been developed to study pharmacokinetics of noscapine at tumor-suppressive doses in the mouse. Since orally available anticancer drugs are rare, therefore, noscapine, an innocuous agent, having a mean oral bioavailability of 31.5% over the studied dose range merits its further advancement in humans for anticancer therapy.