Pharmacokinetics of Rac inhibitor EHop-016 in mice by ultra-performance liquid chromatography tandem mass spectrometry.
Pharmacokinetics of Rac inhibitor EHop-016 in mice by ultra-performance liquid chromatography tandem mass spectrometry.
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DOI：
10.1016/j.jchromb.2014.12.021
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发表时间：
2015-02-15
影响因子：
3
通讯作者：
Dharmawardhane, Suranganie
中科院分区：
文献类型：
--
作者：
Humphries-Bickley, Tessa;Castillo-Pichardo, Linette;Corujo-Carro, Francheska;Duconge, Jorge;Hernandez-O'Farrill, Eliud;Vlaar, Cornelis;Rodriguez-Orengo, Jose F.;Cubano, Luis;Dharmawardhane, Suranganie
Rho GTCRac是癌细胞迁移和侵袭的重要调节因子;转移进展所需的过程。我们先前将小分子EHop-016表征为转移性乳腺癌细胞中的新型Rac抑制剂，并且最近发现EHop-016在25 mg/kg体重（BW）的裸鼠中有效减少肿瘤生长。本研究的目的是比较裸鼠腹膜内（IP）和经口灌胃（PO）给药后，单次给药输入方案（10、20和40 mg/kg BW）中不同剂量EHop-016的药代动力学和生物利用度。我们开发并验证了超高效液相色谱-电喷雾串联质谱（UPLC/MS/MS）定量小鼠血浆中EHop-016的快速灵敏方法。在Agilent Poroshell 120 EC-C18柱（3.0 × 50 mm）上使用有机相和水移动的相进行分离。根据获得的全扫描色谱图的准确质量和保留时间鉴别EHop-016，并通过其峰面积定量。经验证的方法在5 - 1000 ng/mL（1/x2加权）范围内呈线性（R2> 0.995）。使用WinNonlin®通过非房室分析获得药代动力学参数。IP和PO给药的曲线下面积（AUC 0-∞）范围分别为328 - 1869 ng·hr/mL和133 - 487 ng·hr/mL。IP和PO给药的消除半衰期（t1/2）范围分别为3.8 - 5.7小时和3.4 - 26.8小时。对于IP和PO给药，AUC 0-∞值与试验剂量成比例，证明了线性PK特征。口服灌胃给药后EHop-016的相对生物利用度范围为26% -40%。这些结果支持EHop-016作为一种新的抗癌疗法的进一步临床前评价。
The Rho GTPase Rac is an important regulator of cancer cell migration and invasion; processes required for metastatic progression. We previously characterized the small molecule EHop-016 as a novel Rac inhibitor in metastatic breast cancer cells and recently found that EHop-016 was effective at reducing tumor growth in nude mice at 25 mg/kg bodyweight (BW). The purpose of this study was to compare the pharmacokinetics and bioavailability of EHop-016 at different dosages in a single dose input scheme (10, 20 and 40 mg/kg BW) following intraperitoneal (IP) and oral gavage (PO) administration to nude mice. We developed and validated a rapid and sensitive method for the quantitation of EHop-016 in mouse plasma by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC/MS/MS). Separation was carried out on an Agilent Poroshell 120 EC-C18 column (3.0 × 50 mm) using organic and aqueous mobile phases. EHop-016 was identified from its accurate mass and retention time from the acquired full-scan chromatogram and quantified by its peak area. The validated method was linear (R2> 0.995) over the range of 5 – 1000 ng/mL (1/x2 weighting). Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin®. The area under the curve (AUC0-∞) ranged from 328 – 1869 ng·hr/mL and 133 – 487 ng·hr/mL for IP and PO dosing respectively. The elimination half-life (t1/2) ranged from 3.8 – 5.7 hours and 3.4 – 26.8 hours for IP and PO dosing respectively. For both IP and PO administration, the AUC0-∞values were proportional to the tested doses demonstrating linear PK profiles. The relative bioavailability of EHop-016 after oral gavage administration ranged from 26% - 40%. These results support further preclinical evaluation of EHop-016 as a new anti-cancer therapy.
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影响因子：
--
作者：
Want, E;Compton, BJ;Siuzdak, G
通讯作者：
Siuzdak, G
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.5
作者：
WEISS, AJ;MANTHEI, R
通讯作者：
MANTHEI, R
影响因子：
8
作者：
Chan, AY;Coniglio, SJ;Symons, M
通讯作者：
Symons, M
DOI：
10.1186/bcr1329
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Baugher PJ;Krishnamoorthy L;Price JE;Dharmawardhane SF
通讯作者：
Dharmawardhane SF