Determination of a novel anticancer c‐Met inhibitor LS‐177 in rat plasma and tissues with a validated UPLC‐MS/MS method: application to pharmacokinetics and tissue distribution study

Abstract

LS‐177 is a novel small‐molecule kinase inhibitor employed to interrupt the c‐Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated for determination of LS‐177 in rat plasma and tissues. The biosamples were extracted by liquid–liquid extraction with methyl tert‐butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile–0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from −12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS‐177 was stable during the preparation and analytical processes. The UPLC‐MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple‐dose oral administration of LS‐177. The tissue distribution study exhibited significant higher uptakes of LS‐177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application. Copyright © 2014 John Wiley & Sons, Ltd.

Folate-targeted star-shaped cationic copolymer co-delivering docetaxel and MMP-9 siRNA for nasopharyngeal carcinoma therapy

“…DOC concentration in each tissue (liver, kidney, lung, heart, spleen and brain) was assayed according to tert butyl methyl ether extraction method [24], and the standard curves and regression equations were achieved and shown in Electronic Supplementary Information. The mean tissue concentrations of DOC after intravenous administration of the FA-CD-PLLD/DOC/MMP-9 at the DOC dose of 20 mg/kg at different times are shown in Figure 7.…”

“…In vivo target experiment, for DOC distribution analysis, compared to liquid–liquid anhydrous diethyl ether extraction method [28], we found tissue sample extracted by low toxicity tert-butyl methyl ether can be blown dry easily by nitrogen, and the higher DOC extraction rate in tissue was acquired [24]. Because of the two compartment model of drug distribution, after tail intravenous injection, nanomedicines were distributed immediately in central compartment of organs with abundant blood supply such as liver, heart, kidney and so on, concentration of DOC dropped fastly following with accelerated blood flow, and then nanomedicines were distributed slowly in peripheral compartment of organs with less blood flow such as skin, fat, bone and so on, and GFP expression in vivo was similar to DOC distribution.…”

miR‐144‐3p exerts anti‐tumor effects in glioblastoma by targeting c‐Met

“…A novel anti‐cancer MET inhibitor LS‐177 could be distributed in stomach, intestine, lung, and liver among all of the tissues and may provide a meaningful basis for clinical application (Ju et al . ). Dual MET/anaplasticlymphoma kinase (ALK) inhibitor crizotinib, has recently been approved for lung cancers with ALK rearrangement (Schwab et al .…”

Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) in practice: analysis of drugs and pharmaceutical formulations

“…A variety of sample preparation techniques have been applied in a bioanalytical method such as protein precipitation, liquid-liquid extraction, and solid-phase extraction [32]. Among these, the most widely used are protein precipitation and liquid-liquid extraction followed by solid-phase extraction which are used in different category such as antibiotic [33][34][35][36][37][38][39][40], anticancer [36,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62], antiviral [63][64][65][66][67], antifungal [68][69][70][71][72], cardiovascular [73][74][75][76][77]…”