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依鲁替尼及其磷脂复合物在比格犬体内的药动学比较研究
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| 篇名： | 依鲁替尼及其磷脂复合物在比格犬体内的药动学比较研究 |
| TITLE： | |
| 摘要： | 目的：建立测定比格犬血浆中依鲁替尼浓度的方法，并比较依鲁替尼及其磷脂复合物在比格犬体内的药动学差异。结果：将雄性比格犬随机分为依鲁替尼混悬液组和依鲁替尼磷脂复合物组（分别以0.5％交联羧甲基纤维素钠溶液和水为溶剂，质量浓度均为5 mg/mL），每组3只。所有比格犬均单次灌胃相应药物混悬液15 mg/kg，分别于给药前及给药后0.017、0.083、0.25、0.5、1、2、4、8、12 h于左前肢静脉取血2 mL，采用高效液相色谱法（HPLC）测定其血浆中依鲁替尼的质量浓度。以甲苯磺丁脲为内标，色谱柱为Betasil C18，流动相为乙腈-水（含0.5％三乙胺，用冰醋酸调节pH至3.2）（45 ∶ 55，V/V），流速为1.0 mL/min，检测波长为256 nm，柱温为25 ℃，进样量为20 μL。采用DAS 2.1.1软件计算两组比格犬的药动学参数，采用t检验考察两者的差异。结果：依鲁替尼检测血药浓度的线性范围5～5 000 ng/mL（r＝0.999 8），定量下限为5 ng/mL，最低检测限为1.3 ng/mL；批间、批内RSD均小于10％，准确度为98.81％～106.20％，提取方法不影响待测物的测定。单次灌胃依鲁替尼混悬液和依鲁替尼磷脂复合物的tmax分别为（2.00±0.09）、（0.25±0.03）h，cmax分别为（610.67±21.36）、（2 308.72±100.41）ng/mL，AUC0-12 h分别为（4 516.67±383.43）、（9 394.16±874.21）ng·h/mL，AUC0-∞分别为（6 174.32±525.27）、（10 717.33±897.62）ng·h/mL，组间比较差异均有统计学意义（P＜0.05）；依鲁替尼磷脂复合物的相对生物利用度为207.99％。结论：本研究建立的HPLC法操作简便、专属性强、灵敏度高，可用于依鲁替尼血药浓度的测定及药动学的研究。将依鲁替尼制成磷脂复合物后，其药动学参数变化明显，药物吸收明显加快，生物利用度明显提高。 |
| ABSTRACT： | OBJECTIVE： To establish a method for the determination of ibrutinib concentration in Beagle dogs， and to compare the pharmacokinetic difference of ibrutinib and its phospholipid complex in Beagle dogs. METHODS： The male Beagle dogs were randomly divided into Ibrutinib suspension group and Ibrutinib phospholipid complex group （using 0.5％ Carboxymethylcellulose sodium solution and water as solvent， mass concentration of 5 mg/mL）， with 3 dogs in each group. All Beagle dogs were given relevant medicine suspension （15 mg/kg） intragastrically， and 2 mL of blood were collected from the forelimb vein before administration and 0.017， 0.083， 0.25， 0.5， 1， 2， 4， 8 and 12 h after administration. Plasma concentration of ibrutinib was were determined by HPLC. Using tolbutamide as internal standard， the determination was performed on Betasil C18 column with mobile phase consisted of acetonitrile-water （contained 0.5％ triethylamine， pH value adjusted to 3.2 with glacial acetic acid）（45 ∶ 55， V/V） at the flow rate of 1.0 mL/min. The detection wavelength was set at 256 nm， and the column temperature was 25 ℃. The sample size was 20 μL. The pharmacokinetic parameters of Beagle dogs in 2 groups were calculated by using DAS 2.1.1 software. The difference of ibrutinib and its phospholipid complex were investigated by t-test. RESULTS： The linear range of ibrutinib was 5-5 000 ng/mL （r＝0.999 8）； lower limit of quantitation was 5 ng/mL； minimum detection limit was 1.3 ng/mL. RSDs of intra-batch and inter-batch were lower than 10％； the accuracy was 98.81％-106.20％； the extraction method did not influence the determination of the substance to be measured. Pharmacokinetic parameters of Ibrutinib suspension and Ibrutinib phospholipid complex with signal intragastric administration were as follows： tmax were（2.00±0.09） and （0.25±0.03）h； cmax were（610.67±21.36） and （2 308.72±100.41）ng/mL； AUC0-12 h were （4 516.67±383.43） and （9 394.16±874.21）ng·h/mL； AUC0-∞ were （6 174.32±525.27） and （10 717.33±897.62）ng·h/mL，with statistical significance （P＜0.05）. The relative bioavailability of Ibrutinib phospholipid complex was 207.99％. CONCLUSIONS： Established HPLC method is simple， specific and sensitive， and can be used for plasma concentration determination and pharmacokinetic study of ibrutinib. The pharmacokinetic parameters of phospholipid complex prepared from ibrutinib changed significantly， drug absorption is accelerated and bioavailability is improved significantly. |
| 期刊： | 2019年第30卷第14期 |
| 作者： | 林琳，鲁梅，邓意辉 |
| AUTHORS： | LIN Lin，LU Mei，DENG Yihui |
| 关键字： | 依鲁替尼；磷脂复合物；药动学；生物利用度；比格犬；比较研究 |
| KEYWORDS： | Ibrutinib； Phospholipid complex； Pharma- cokinetics； Bioavailability； Beagle dog； Comparative study |
| 阅读数： | 385 次 |
| 本月下载数： | 7 次 |
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