高效液相色谱法测定大鼠血浆中阿昔洛韦浓度及其与吉非替尼药物相互作用的研究

doi:10.5246/jcps.2021.06.038

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (6): 495-504.DOI: 10.5246/jcps.2021.06.038

高效液相色谱法测定大鼠血浆中阿昔洛韦浓度及其与吉非替尼药物相互作用的研究

李莹¹, 文周³, 刘永玲¹, 赵治兵¹, 王磊²^,³^,^*(), 程泽能³^,^*

1. 1. 贵阳学院食品与制药工程学院, 贵州贵阳 550005
2. 中南大学生命科学学院, 湖南长沙 410013
3. 中南大学药学院, 湖南长沙 410013

收稿日期:2020-11-23 修回日期:2021-02-18 接受日期:2021-04-15 出版日期:2021-06-29 发布日期:2021-06-29
通讯作者: 王磊, 程泽能
作者简介:
+ Tel.: +86-731-82650446, Fax: +86-731-82650451, E-mail: wangleivvl@163.com
+ Tel.: +86-731-82650446, Fax: +86-731-82650451
基金资助:
Discipline and Master’s Site Construction Project of Guiyang University by Guiyang City Financial Support Guiyang University (Grant No. SY-2020) and Guizhou Biopharmaceutical Engineering Research Center (Grant No. QJH KYZ [2019] 051).

A new sample preparation method for the determination of acyclovir by RP-HPLC: application to a drug-drug interaction study between gefitinib and acyclovir in rats

Ying Li¹, Zhou Wen³, Yongling Liu¹, Zhibing Zhao¹, Lei Wang²^,³^,^*(), Zeneng Cheng³^,^*

1 Food and Pharmaceutical Engineering Institute, Guiyang University, Guiyang 550005, China
2 School of Life Sciences, Central South University, Changsha 410013, China
3 School of Pharmaceutical Sciences, Central South University, Changsha 410013, China

Received:2020-11-23 Revised:2021-02-18 Accepted:2021-04-15 Online:2021-06-29 Published:2021-06-29
Contact: Lei Wang, Zeneng Cheng

摘要/Abstract

摘要：

由于阿昔洛韦水溶性高, 较难用普通高效液相色谱法测定其血浆中的药物浓度。本研究建立并验证了测定大鼠血浆中阿昔洛韦浓度的高效液相色谱方法, 并将该方法应用于与吉非替尼的药物相互作用研究中。采用Platisil ODS柱(4.6 mm × 250 mm, 5 μm, 迪马科技), 检测波长254 nm, 蛋白沉淀后再用甲基叔丁基醚萃取进行样本处理。阿昔洛韦浓度在0.2–40 μg/mL范围内具有良好的线性关系(r² = 0.9999), 本方法批间和批内精密度均小于8%, 批间和批内准确度偏差不超过10%。该方法已成功应用于大鼠体内吉非替尼和阿昔洛韦的药物相互作用研究中。结果显示, 同时服用吉非替尼可使阿昔洛韦的吸收增加3倍, 这为临床表皮生长因子-酪氨酸酶抑制剂与阿昔洛韦的合用提供了参考。

关键词: 阿昔洛韦, 高效液相色谱法, 样本处理, 吸收, 药物相互作用

Abstract:

The assay of acyclovir in plasma seems to be a challenge because of its high hydrophily. In our present study, a reversed-phase high-performance liquid chromatography (RP-HPLC) method for the determination of acyclovir in rat plasma was described and validated in drug-drug interaction (DDI) between gefitinib and acyclovir in rats. The analytes were separated with gradient elution on C₁₈ column (4.6 mm × 250 mm, 5 μm), and the peaks were recorded using ultraviolet detector at a wavelength of 254 nm. Protein precipitation followed by methyl tertiary butyl ether extraction was used for sample preparation. The calibration curve was established between 0.2 and 40 μg/mL (r² = 0.9999). The intra- and inter-day precisions were all less than 8%, and all the biases were not more than 10%. This new method was successfully applied to a DDI study between gefitinib and acyclovir in rats. Gefitinib up-regulated the absorption of acyclovir by about three times, and our findings guided the clinical co-administration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with acyclovir.

Key words: Acyclovir, High-performance liquid chromatography, Sample preparation, Absorption, Drug-drug interaction

Supporting:

李莹, 文周, 刘永玲, 赵治兵, 王磊, 程泽能. 高效液相色谱法测定大鼠血浆中阿昔洛韦浓度及其与吉非替尼药物相互作用的研究[J]. 中国药学(英文版), 2021, 30(6): 495-504.

Ying Li, Zhou Wen, Yongling Liu, Zhibing Zhao, Lei Wang, Zeneng Cheng. A new sample preparation method for the determination of acyclovir by RP-HPLC: application to a drug-drug interaction study between gefitinib and acyclovir in rats[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(6): 495-504.

图/表 6

Figure 1. Chemical structures of (A) acyclovir and (B) entecavir.

Figure 2. Typical chromatograms of acyclovir in rat plasma: (A) Blank rat plasma; (B) Blank plasma spiked with acyclovir (5 μg/mL) and IS; (C) Plasma sample from rat 4 h after oral administration of 300 mg/kg acyclovir suspension.

Table 1. Intra- and inter-day accuracy and precision of acyclovir in rat plasma.

Table 2. Stability of acyclovir in rat plasma under various conditions (n = 3).

Table 3. The pharmacokinetic parameters of acyclovir with and without the co-administration of gefitinib (n = 6).

Figure 3. Gefitinib increased the absorption of acyclovir in rats. Error bars represented the standard error of the mean (n = 6).

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高效液相色谱法测定大鼠血浆中阿昔洛韦浓度及其与吉非替尼药物相互作用的研究

A new sample preparation method for the determination of acyclovir by RP-HPLC: application to a drug-drug interaction study between gefitinib and acyclovir in rats

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