Mengchun Chen

Wenzhou Medical University

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Yijie Chen

Wenzhou Medical University

Guoxin Hu

Wenzhou Medical University

Qingqing Yin

University of Pittsburgh

De‐Li ZhuGe

Wenzhou Medical University

Xianqin Wang

Wenzhou Medical University

Ying‐Zheng Zhao

Wenzhou Medical University

Dongyan Tian

Wenzhou Medical University

Xuewei Yang

Wenzhou Medical University

Cuiye Weng

Wenzhou Medical University

Haonan Wang

Fudan University

Cooperative Institutions

Wenzhou Medical University

134

Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University

First Affiliated Hospital of Wenzhou Medical University

Shanghai Jiao Tong University

Zhejiang University

University of California, San Diego

Chinese Academy of Sciences

Wenzhou University

Peking University

Chinese Academy of Medical Sciences & Peking Union Medical College

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Determination of chidamide in rat plasma by LC‐MS and its application to pharmacokinetics study

Biomedical Chromatography (2013)

Xianqin Wang Mengchun Chen Congcong Wen Qingwei Zhang Jianshe Ma

ABSTRACT A sensitive and selective liquid chromatography mass spectrometry method for determination of chidamide in rat plasma was developed. After addition of linezolid as internal standard, protein precipitation by acetonitrile–methanol (9:1, v/v) was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB‐C 18 (2.1 × 150 mm, 5 µm) column with acetonitrile–0.1% formic acid as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification using target fragment ions m / z 391.5 for chidamide and m / z 338.5 for the IS. Calibration plots were linear over the range of 10–2000 ng/mL for chidamide in rat plasma. The lower limit of quantification for chidamide was 10 ng/mL. The mean recovery of chidamide in plasma was in the range of 86.6–92.1%. The coefficients of variation of intra‐day and inter‐day precision were both <12%. This method is simple and sensitive and was applied successfully in a pharmacokinetic study of chidamide to rats. Copyright © 2013 John Wiley & Sons, Ltd.

Protein precipitation

10.1002/bmc.3001

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Citations (19)

Comparison of the inhibitory effect of ketoconazole, voriconazole, fluconazole, and itraconazole on the pharmacokinetics of bosentan and its corresponding active metabolite hydroxy bosentan in rats

Xenobiotica (2019)

Mengchun Chen Xufei Zhang Yijie Chen Wei Sun Zhe Wang

1. This study aimed to investigate the inhibitory effect of azole antifungal agents, including ketoconazole, voriconazole, fluconazole, and itraconazole, on the pharmacokinetics of bosentan (BOS) and its active metabolite hydroxy bosentan (OHBOS) in Sprague-Dawley (SD) rats.2. A total of 25 healthy male SD rats were divided into five groups and treated with various azole antifungal agents by gavage, followed by a single dose of BOS after 30 min.3. The study found that ketoconazole led to a significant increase (5.1-fold) in the AUC(0-t) of BOS, associated with a 5.8-fold elevation in the Cmax, which was greater than that for fluconazole (2.6- and 2.9-fold) and voriconazole (1.1- and 1.7-fold). Accordingly, the Vz/F and CLz/F of BOS reduced by 89.2% and 83.7%, respectively, on administering ketoconazole concomitantly. However, fluconazole caused a decrease in Vz/F and CLz/F by 77.4% and 72.2%, respectively, compared with voriconazole that exhibited a decrease in CLz/F by 51.7% with a negligible change in Vz/F. Also, obvious differences were observed in the pharmacokinetic parameters of OHBOS between the control and treated groups.4. Collectively, treatment with ketoconazole resulted in a prominent inhibitory effect on the metabolism of BOS, followed by treatment with fluconazole, voriconazole, and itraconazole. Therefore, these details of animal studies may help draw more attention to the safety of BOS while combining it with ketoconazole, voriconazole, fluconazole, or itraconazole clinically.

Azole

Active metabolite

10.1080/00498254.2019.1628321

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Pharmacokinetic interaction of entinostat and lapatinib following single and co-oral administration in rats

Xenobiotica (2014)

Xuezhi Yang Qingwei Zhang Mengchun Chen Lufeng Hu

1. Entinostat, also known as SNDX-275 or MS-275, is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has show that MS-275 can enhance the activity of lapatinib in HER(2+) metastatic inflammatory and non-inflammatory breast cancer. This study examined whether oral administration of MS-275 to the rats with lapatinib led to any pharmacokinetic interactions. 2. To evaluate pharmacokinetic interaction of MS-275 and lapatinib in rat, a sensitive and simple LC-MS method was developed to simultaneously determine MS-275 and lapatinib in rat plasma with carbamazepine as internal standard (IS). Eighteen rats were divided randomly into three groups, lapatinib group (lapatinib 15 mg/kg, n = 8), MS-275 group (MS-275 15 mg/kg, n = 8) and co-administration group (MS-275 15 mg/kg and lapatinib 15 mg/kg, n = 8). 3. There was no statistical pharmacokinetics difference for MS-275 in MS-275 group and co-administration group; the lapatinib could not influence the pharmacokinetic profile of MS-275 in rats. However, there is a statistical pharmacokinetics difference between lapatinib in the lapatinib group and co-administration group, when co-oral administration MS-275 with lapatinib, AUC increased from 2375.5 to 9900.3 ng/mL h (p < 0.05), Cmax increased from 538.0 to 2578.2 ng/mL (p < 0.01), CL decreased from 6.2 to 1.7 L/h/kg (p < 0.01). 4. These data indicate MS-275 could obviously influence the pharmacokinetic profile of lapatinib in rats, which might cause drug-drug interactions in humans when using lapatinib with MS-275. Further investigations should be carried out to elucidate the synergistic mechanisms between the two drugs.

Lapatinib

10.3109/00498254.2014.919431

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The Effects of Acute Hydrogen Sulfide Poisoning on Cytochrome P450 Isoforms Activity in Rats

BioMed Research International (2014)

Xianqin Wang Mengchun Chen Xinxin Chen Jianshe Ma Congcong Wen

Hydrogen sulfide (H 2 S) is the second leading cause of toxin related death (after carbon monoxide) in the workplace. H 2 S is absorbed by the upper respiratory tract mucosa, and it causes histotoxic hypoxemia and respiratory depression. Cocktail method was used to evaluate the influences of acute H 2 S poisoning on the activities of cytochrome P450 isoforms CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19, and CYP2C9, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs, bupropion, metoprolol, midazolam, phenacetin, omeprazole, and tolbutamide, respectively. The experimental rats were randomly divided into two groups, control group and acute H 2 S poisoning group (inhaling 300 ppm for 2 h). The mixture of six probes was given to rats by oral administration and the blood samples were obtained at a series of time points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by LC-MS. The results for acute H 2 S poisoning and control groups were as follows: there was a statistically significant difference in the AUC andCmaxfor bupropion, metoprolol, phenacetin, and tolbutamide, while there was no statistical pharmacokinetic difference for midazolam and omeprazole. Acute H 2 S poisoning could inhibit the activity of CYP2B6, CYP2D6, CYP1A2, and CYP2C9 in rats.

10.1155/2014/209393

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Establishment and validation of an innovative UPLC-MS/MS approach for quantitation and pharmacokinetics of veliparib in rat plasma

Acta Chromatographica (2024)

Mengming Xia Shunjun Ma Wanhang Wang Dizhong Chen Mengchun Chen

Abstract In this investigation, a rapid and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed for quantification of veliparib in rat plasma and used the method to study the pharmacokinetics and bioavailability of veliparib in rats after oral (6 mg kg −1 ) and intravenous (2 mg kg −1 ) administration. Plasma samples were protein precipitated with acetonitrile using midazolam as internal standard. A UPLC HSS T3 chromatographic column was utilized for separation, with a mobile phase consisting of methanol-water-formic acid in gradient elution procedure. Quantitative analysis was performed using multiple reaction monitoring in electrospray positive-ion mode. Veliparib exhibited excellent linearity within the 1–1,000 ng mL −1 range ( r > 0.99). The intra- and inter-day precision of veliparib were both within 15%, and the accuracy ranged from 93.7 to 107.7%. The average recovery was above 86%, and the matrix effect was 89.0–95.8%. The AUC (0-t) values for oral and intravenous administration were 1014.7 ± 42.9 and 647.2 ± 85.2 h ng mL −1 , respectively, resulting in a bioavailability of 52.3%. The UPLC-MS/MS method established in this study featured a low sample injection volume, a low quantification limit, a short chromatographic runtime, high sensitivity, and selectivity. The developed method can be used for the pharmacokinetic analysis of veliparib in both preclinical and clinical studies.

Veliparib

10.1556/1326.2024.01230

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Remote Loading of Small‐Molecule Therapeutics into Cholesterol‐Enriched Cell‐Membrane‐Derived Vesicles

Angewandte Chemie International Edition (2017)

Xinxin Zhang Pavimol Angsantikul Man Ying Jia Zhuang Qiangzhe Zhang

The increasing popularity of biomimetic design principles in nanomedicine has led to therapeutic platforms with enhanced performance and biocompatibility. This includes the use of naturally derived cell membranes, which can bestow nanocarriers with cell-specific functionalities. Herein, we report on a strategy enabling efficient encapsulation of drugs via remote loading into membrane vesicles derived from red blood cells. This is accomplished by supplementing the membrane with additional cholesterol, stabilizing the nanostructure and facilitating the retention of a pH gradient. We demonstrate the loading of two model drugs: the chemotherapeutic doxorubicin and the antibiotic vancomycin. The therapeutic implications of these natural, remote-loaded nanoformulations are studied both in vitro and in vivo using animal disease models. Ultimately, this approach could be used to design new biomimetic nanoformulations with higher efficacy and improved safety profiles.

Cell membrane

Lipid vesicle

10.1002/anie.201707598

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Citations (97)

A Methodology for Quantitation of Dictamnine and Fraxinellone and its Application to Study Pharmacokinetics and Bioavailability in Rats Via Oral and Intravenous Administration

Journal of Chromatographic Science (2022)

Mengchun Chen Xiuwei Shen Xuewei Yang Qingqing Yin Dongyan Tian

The pharmacological activities of dictamnine and fraxinellone have been well reported; however, only a few studies have focused on the pharmacokinetics and bioavailability of concomitant delivery of these drugs in vivo. To shed light on this neglected area, we developed a rapid and sensitive UPLC-MS/MS method that quantified the levels of dictamnine and fraxinellone simultaneously in rat plasma. This method was initiated by a one-step protein precipitation strategy to purify plasma samples collected from rats treated with either oral or intravenous administration of dictamnine and fraxinellone. The mobile phase contained acetonitrile and 0.1% formic acid at a steady flow rate of 0.6 mL/min. As a result, an excellent analyte peak resolution was achieved, and the entire process took only 3 min per sample. The results were indicative of the desired linearity (r2 ≥ 0.999), precision (RSD% was within 15%), accuracy (RE% was within 15%), recoveries (≥80.66 and 68.15% for dictamnine and fraxinellone, respectively) and matrix effects (≥94.66 and 91.37% for dictamnine and fraxinellone, respectively). Additionally, the detectable limits of these two compounds were both low even when they reached 5 ng/mL. Taken together, these findings contribute to a better understanding of the pharmacokinetics and bioavailability properties of concomitant delivery of dictamnine and fraxinellone.

Protein precipitation

10.1093/chromsci/bmac053

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Citations (1)

The role of CYP2C9 genetic polymorphisms in the oxidative metabolism of diclofenac in vitro.

PubMed (2014)

Mengming Xia Li Wang Pei-Pei PAan Haiyun Wang Mengchun Chen

CYP2C9 is one of four known members of the human cytochrome P450 CYP2C superfamily, with at least 57 CYP2C9 alleles being previously identified. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The purpose of the present study was to clarify the role of 36 CYP2C9 alleles, 21 novel alleles (*36-*56) found in the Chinese population, in the oxidative metabolism of diclofenac in vitro. Insect microsomes expressing the 36 human CYP2C9 alleles were incubated with 2-100 μM diclofenac for 30 min at 37 degrees C and terminated by the addition of 30 μL 0.1 M HCl. Diclofenac and 4'-hydroxyl (OH)-diclofenac, the major diclofenac metabolite, were analyzed by high-performance liquid chromatography (HPLC). Compared with wild-type CYP2C9*1, most variants showed significantly altered values in V(max), K(m) and intrinsic clearance (V(max)/K(m)). Only one variant exhibited markedly increased intrinsic clearance value, whereas 31 variants exhibited significantly decreased values. Thus, this study demonstrated that more attention should be given to subjects carrying these CYP2C9 alleles when administering diclofena.

Diclofenac

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Determination of emodin, chrysophanol, and physcion by HPLC in the chinese medicine rumex japonicus houtt.

Latin American Journal of Pharmacy (2012)

Chongliang Lin Mengchun Chen Jinzhang Cai Minmin Lai Yiting Zheng

Rumex

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Effect of CYP2C9 genetic polymorphism on the metabolism of flurbiprofenin vitro

Drug Development and Industrial Pharmacy (2014)

Li Wang Shi-Hui Bao Peipei Pan Mengming Xia Mengchun Chen

CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, and 57 cytochrome P450 2C9 alleles have been previously reported. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for 4′-hydroxyflurbiprofen were determined using recombinant human P450s CYP2C9 microsomes from insect cells Sf21 carrying wild-type CYP2C9*1 and other variants. The results showed that the enzyme activity of most of the variants decreased comparing with the wild type as the previous studies reported, while the enzyme activity of some of them increased, which were not in accordance with the previous researches. Of the 36 tested CYP2C9 allelic isoforms, two variants (CYP2C9*53 and CYP2C9*56) showed a higher intrinsic clearance value than the wild-type protein, especially for CYP2C9*56, exhibited much higher intrinsic clearance (197.3%) relative to wild-type CYP2C9*1, while the remaining 33 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.6 to 83.8%) compared to CYP2C9*1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used non-steroidal anti-inflammatory drug, flurbiprofen (FP). The results indicated that most of the tested rare alleles decreased the catalytic activity of CYP2C9 variants toward FP hydroxylation in vitro. This is the first report of all these rare alleles for FP metabolism providing fundamental data for further clinical studies on CYP2C9 alleles for FP metabolism in vivo.

Wild type

10.3109/03639045.2014.950274

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Citations (22)