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Pharmacokinetics of the Rac/Cdc42 Inhibitor MBQ-167 in Mice by Supercritical Fluid Chromatography-Tandem Mass Spectrometry.
ACS Omega ( IF 3.7 ) Pub Date : 2019-10-23 , DOI: 10.1021/acsomega.9b01641 María Del Mar Maldonado 1 , Gabriela Rosado-González 1, 2 , Joseph Bloom 1 , Jorge Duconge 1 , Jean F Ruiz-Calderón 1 , Eliud Hernández-O'Farrill 1 , Cornelis Vlaar 1 , José F Rodríguez-Orengo 1, 3 , Suranganie Dharmawardhane 1
ACS Omega ( IF 3.7 ) Pub Date : 2019-10-23 , DOI: 10.1021/acsomega.9b01641 María Del Mar Maldonado 1 , Gabriela Rosado-González 1, 2 , Joseph Bloom 1 , Jorge Duconge 1 , Jean F Ruiz-Calderón 1 , Eliud Hernández-O'Farrill 1 , Cornelis Vlaar 1 , José F Rodríguez-Orengo 1, 3 , Suranganie Dharmawardhane 1
Affiliation
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The Rho GTPases Rac and Cdc42 are potential targets against metastatic diseases. We characterized the small molecule MBQ-167 as an effective dual Rac/Cdc42 inhibitor that reduces HER2-type tumor growth and metastasis in mice by ∼90%. This study reports the pharmacokinetics and tissue distribution of MBQ-167 following intraperitoneal and oral single-dose administrations. We first developed and validated a bioanalytical method for the quantitation of MBQ-167 in mouse plasma and tissues by supercritical fluid chromatography coupled with electrospray ionization tandem mass spectrometry. MBQ-167 was rapidly distributed into the kidneys after intraperitoneal dosing, whereas oral administration resulted in higher distribution to lungs. The elimination half-lives were 2.17 and 2.6 h for the intraperitoneal and oral dosing, respectively. The relative bioavailability of MBQ-167 after oral administration was 35%. This investigation presents the first analysis of the pharmacokinetics of MBQ-167 and supports further preclinical evaluation of this drug as a potential anticancer therapeutic.
中文翻译：
超临界流体色谱-串联质谱法研究Rac / Cdc42抑制剂MBQ-167在小鼠中的药代动力学。
Rho GTPases Rac和Cdc42是对抗转移性疾病的潜在靶标。我们将小分子MBQ-167表征为有效的Rac / Cdc42双重抑制剂，可将HER2型肿瘤在小鼠中的生长和转移降低约90％。这项研究报告了腹膜内和口服单剂量给药后MBQ-167的药代动力学和组织分布。我们首先开发和验证了一种通过超临界流体色谱结合电喷雾电离串联质谱法定量测定小鼠血浆和组织中MBQ-167的生物分析方法。腹膜内给药后，MBQ-167迅速分布到肾脏中，而口服给药导致向肺中的分布更高。腹膜内和口服给药的消除半衰期分别为2.17和2.6小时。口服后MBQ-167的相对生物利用度为35％。这项研究提出了对MBQ-167药代动力学的首次分析，并支持对该药物作为潜在的抗癌治疗剂进行进一步的临床前评估。
更新日期：2019-11-05
中文翻译：
超临界流体色谱-串联质谱法研究Rac / Cdc42抑制剂MBQ-167在小鼠中的药代动力学。
Rho GTPases Rac和Cdc42是对抗转移性疾病的潜在靶标。我们将小分子MBQ-167表征为有效的Rac / Cdc42双重抑制剂，可将HER2型肿瘤在小鼠中的生长和转移降低约90％。这项研究报告了腹膜内和口服单剂量给药后MBQ-167的药代动力学和组织分布。我们首先开发和验证了一种通过超临界流体色谱结合电喷雾电离串联质谱法定量测定小鼠血浆和组织中MBQ-167的生物分析方法。腹膜内给药后，MBQ-167迅速分布到肾脏中，而口服给药导致向肺中的分布更高。腹膜内和口服给药的消除半衰期分别为2.17和2.6小时。口服后MBQ-167的相对生物利用度为35％。这项研究提出了对MBQ-167药代动力学的首次分析，并支持对该药物作为潜在的抗癌治疗剂进行进一步的临床前评估。
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