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Disposition and fate of polyoxyethylene glycerol ricinoleate as determined by LC-Q-TOF MS coupled with MS^(ALL),SWATH and HR MS/MS techniques

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Chinese Chemical Letters 2021年第10期32卷 3237-3240页

作者： Ruifeng Bai Dong Sun Yuqin Shan Zhiqiong Guo Dafeng Chu John Paul Fawcett Jingkai Gu center for drug metabolism research School of Life SciencesJilin UniversityChangchun 130012China

Polyoxyethylene glycerol ricinoleate(PGR) serves as a solubilizer/emulsifier that is commonly used in pharmaceutical formulations despite being associated with severe anaphylactoid hypersensitivity *** EL?(CrEL) is the most representative PGR produced from reacting ethylene oxide with castor *** help clarify the cause of side effects and potentially improve the safety of PGR-based drug delivery vehicle,we have developed separate but related analytical methods for the quantitation of CrEL and its main metabolites,glycerol ethoxylate(GE) and ricinoleic acid(RA).Since CrEL and GE are highly disperse mixtures of polymers that are not amenable to analysis by conventional liquid chromatographytandem mass spectrometry(LC-MS/MS),we used liquid chromatography-triple-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF MS) combined with product ion data acquisition by MSALLand sequential window acquisition of all theoretical fragments mass spectrometry(SWATH MS),respectively to perform the *** contrast,RA is a single molecular entity that could be readily analyzed using conventional LC-HR MS/*** of specific fragment ions for CrEL,GE,RA and their internal standards enabled a precise quantitation of such a complex analytes system in rat plasma after a single and simple sample preparation *** validation indicated linearity for CrEL,GE and RA over the concentration ranges 0.2~20.0 μg/mL,0.1~10.0 μg/mL and 0.1~20.0 μg/m L,respectively with satisfactory results for other validation parameters.A subsequent pharmacokinetic study involving single intravenous 200 mg/kg injections of CrEL to rats showed the methods enable comprehensive and high throughput quantitation of CrEL and its metabolites in a biological *** combination of assays provides effective application in investigating the cause of the hypersensitivity reaction of PGR and potentially to improve its safety for using as a vehicle in drug formulations.

关键词： Polyoxyethylene glycerol ricinoleate Cremophor EL LC-Q-TOF MS Glycerol ethoxylate Ricinoleic acid

Rapid and Sensitive Liquid Chromatography-Tandem Mass Spectrometry for Quantification of Glycyrrhetic Acid in Human Plasma

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Chemical research in Chinese Universities 2011年第2期27卷 185-189页

作者： TIAN Li GAO Xtao-li CHEN Xiao-yan ZHONG Da-fang ZHANG Yi-fan DAI Xiao-jian College of Trditional Chinese Medicine 2. College of Pharmacy Xinjiang Medical University Urumqi 830011 P R. China center for drug metabolism and pharmacokinetic research Shanghai 201203 P. R. China

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry（LC-MS/MS） for the determination of glycyrrhetic acid in human plasma with ginsenoside Rh2 as internal standard was developed and validated. The plasma samples were prepared via liquid-liquid extraction with ethyl acetate. Chromatographic separation was accomplished on a Venusil MP-C18（50 mm×2.1 mm, 5 μm i.d.） column at 25 °C. The mobile phase consisted of acetonitrile/5 mmol？L-1 ammonium acetate（10：90, volume ratio） at a flow rate of 0.4 mL/min. Negative electrospray ionization was utilized as the ionization source. Glycyrrhetic acid and internal standard were determined via the mutiple reaction monitoring of precursor→production ion transitions at m/z 469→425, 409 and m/z 621→161, respectively. Each sample was chromatographed within 2.5 min. The lower limit of quantification was 0.50 ng/mL for 200 μL of plasma sample and the linear range was from 0.50 ng/mL to 800 ng/mL. The intra- and inter-day precisions were less than 8.76% in terms of relative standard deviation（RSD）, and the accuracy was within a range of -3.25%-1.32% in terms of relative error（RE）. The method was successfully applied to the pharmacokinetic studies of glycyrrhetic acid in healthy male Chinese volunteers after a single oral administration of 75 mg of glycyrrhizin.

关键词： Liquid chromatography-tandem mass spectrometry(LC-MS/MS) Glycyrrhetic acid pharmacokinetics

Effect of baicalin and berberine on transport of nimodipine on primarycultured,rat brain microvascular endothelial cells

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Acta Pharmacologica Sinica 2007年第4期28卷 573-578页

作者： Dong-mei ZHANG Hai-yan LIU Lin XIE Xiao-dong LIU center of drug metabolism and pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China center of drug metabolism and pharmacokinetics China Pharmaceutical University Nanjing China

Aim:To investigate whether baicalin and berberine affects the transport ofnimodipine (NMD) across the blood-brain barrier (BBB).Methods:Primary-cultured,rat brain microvascular endothelial cells (rBMEC) were used as an invitro model of the *** cells became confluent,the steady-state uptake ofNMD by rBMEC with or without baicalin and berberine was *** ef-fects of baicalin and berberine on the efflux of NMD from rBMEC were also ***:Baicalin (2-5 μg/mL) increased the uptake of NMD,and baicalin (10-20μg/mL) decreased the *** steady-state uptake of NMD was higher thanthat of control group in the presence of 0.01-1 μg/mL berberine,but was lower inthe presence of 2-10 μg/mL ***:The bidirectional effect ofbaicalin and berberine on the uptake of NMD by rBMEC was *** showed an inhibitory effect,and lower concentration demonstratedan increasing effect.

关键词： nimodipine baicalin berberine P-glycoprotein

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for Molecular Innovation and drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)in rat

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Acta Pharmaceutica Sinica B 2021年第4期11卷 1003-1009页

作者： Xiangjun Meng Zhi Zhang Jin Tong Hui Sun John Paul Fawcett Jingkai Gu research center for drug metabolism School of Life SciencesJilin UniversityChangchun 130012China Beijing Institute of drug metabolism Beijing 102209China School of Pharmaceutical Sciences Tsinghua UniversityBeijing 100084China

Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)(PEG-PLA)is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier(nanocarrier)in drug *** the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery ***,acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of *** this study,the pharmacokinetics,biodistribution,metabolism and excretion of PEG-PLA were investigated in rat after intravenous *** results show that unchanged PEG-PLA is mainly distributed to spleen,liver,and kidney before being eliminated in urine over 48 h mainly(>80%)in the form of its PEG *** study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientifc design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.

关键词： Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) Polymer Nanocarrier material pharmacokinetics Biodistribution metabolism Excretion Rat

Transport of carbamazepine and drug interactions at blood-brain barrier

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Acta Pharmacologica Sinica 2006年第2期27卷 249-253页

作者： jing-jing SUN Lin XIE Xiao-dong LIU~2 center of drug metabolism and pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China center of drug metabolism and pharmacokinetics China Pharmaceutical University Nanjing China

Aim:To investigate the characteristics of carbamazepine(CBZ)transport anddrug interactions at the blood-brain ***:Cultured rat brain microvas-cular endothelial cells(rBMEC)were used as an in vitro model of the blood-brainbarrier(BBB).When cells became confluent,CBZ uptake over time was recordedby incubation of the cells in a medium containing 10 mg/L CBZ at 37℃.Thesteady-state uptake of CBZ by rBMEC was tested for different CBZ concentra-tions at 37℃.The effects of various agents on the steady-state uptake of CBZand efflux of CBZ from rBMEC were also ***:The uptake of CBZ byrBMEC was time-and *** steady-state uptake oc-curred at 30 rain for *** steady-state uptake was significantly in-creased(P<0.01)by treatment with *** co-administration ofcyclosporine A significantly increased the steady-state uptake of CBZ by therBMEC,whereas co-administration of olanzapine significantly decreased the up-take in a concentration-and temperature-dependent *** efflux of CBZfrom rBMEC was inhibited by ***:The transport of CBZ at the BBBis mediated by many *** specific ABC(ATP-binding cassette,ABC)efflux transporters may be involved in the transport of *** influ-ence the transport of CBZ at the BBB in different ways.

关键词： carbamazepine blood-brain barrier cyclosporine A olanzapine rat brain microvascular endothelial cells drug interaction

Influence of dosage forms on pharmacokinetics of daidzein and its main metabolite daidzein-7-O-glucuronide in rats

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Acta Pharmacologica Sinica 2005年第9期26卷 1145-1152页

作者： Feng QIU~2 Xiao-yan CHEN~2 Bo SONG~2 Da-fang ZHONG~3 Chang-xiao LIU~4 2 Laboratory of drug metabolism and pharmacokinetics,Shenyang Pharmaceutical University,Shenyang 110016,China Laboratory of drug metabolism and pharmacokinetics Shenyang Pharmaceutical University Shenyang China Tianjin Key Laboratory of drug metabolism and pharmacokinetics Tianjin Institute of Pharmaceutical Research Tianjin China

Aim:To investigate the influence of dosage forms on the pharmacokinetics ofdaidzein and its main metabolite daidzein-7-O-glucuronide in Wistar ***:After administration of two typical dosage forms(daidzein solution andsuspension),the concentrations of daidzein and daidzein-7-O-glucuronide weredetermined by an LC-MS-MS *** pharmacokinetic parameters were cal-culated and analyzed statistically using the Student’s ***:Absorp-tion of daidzein after administration of daidzein solution(tmax=0.46 h)was morerapid than that of the suspension(tmax=5.00 h).The peak plasma concentrationsof daidzein after administration of daidzein solution and suspension were 601.1 μg/Land 127.3 μg/L,respectively,and those of daidzein-7-O-glucuronide were 3000 μg/Land 192.6 μg/L,*** absolute bioavailabilities of free daidzein in ratsafter administration of daidzein solution and suspension were 12.8% and6.1%,respectively,which were calculated to be 47.0% and 12.2%,respectively,inthe form of total daidzein(free plus conjugated daidzein).Conclusion:Absorp-tion of daidzein solution was better than absorption of suspension(P<0.05).

关键词： daidzein daidzein-7-O-glucuronide influence dosage forms pharmacokinetics rats

Antioxidant therapy in the management of acute,chronic and post-ERCP pancreatitis:A systematic review

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World Journal of Gastroenterology 2009年第36期15卷 4481-4490页

作者： Seyed Sajad Mohseni Salehi Monfared Hamed Vahidi Amir Hossein Abdolghaffari Shekoufeh Nikfar Mohammad Abdollahi Endocrinology and metabolism research Centre Tehran University of Medical Sciences Student Scientific research center Tehran University of Medical Science Pharmaceutical Sciences research center Tehran University of Medical Sciences Food&drug Affairs and Food&drug Laboratory research center Ministry of Health&Medical Education Faculty of Pharmacy and Pharmaceutical Sciences research center and Endocrinology&Metabolism Research CentreTehran University of Medical Sciences

We systematically reviewed the clinical trials which recruited antioxidants in the therapy of pancreatitis and evaluated whether antioxidants improve the outcome of patients with pancreatitis. Electronic bibliographic databases were searched for any studies which investigated the use of antioxidants in the management of acute pancreatitis （AP） or chronic pancreatitis （CP） and in the prevention of post-endoscopic retrograde cholangio-pancreatography （post-ERCP） pancreatitis （PEP） up to February 2009. Twenty-two randomized, placebo-controlled, clinical trials met our criteria and were included in the review. Except for a cocktail of antioxidants which showed improvement in outcomes in three different clinical trials, the results of the administration of other antioxidants in both AP and CP clinical trials were incongruent and ***, antioxidant therapy including allopurinol and N-acetylcysteine failed to prevent the onset of PEP in almost all trials. In conclusion, the present data do not support a benefit of antioxidant therapy alone or in combination with conventional therapy in the management of AP, CP or PER Further double blind, randomized, placebo-controlled clinical trials with large sample size need to be conducted.

关键词： Antioxidant Post-endoscopic retrogradecholangio-pancreatography pancreatitis Oxidative stress,Therapy Acute pancreatitis Chronic pancreatitis

Biological fate and interaction with cytochromes P450 of the nanocarrier material,D-α-tocopheryl polyethylene glycol 1000 succinate

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3156-3166页

作者： Tianming Ren Runzhi Li Liqiang Zhao J.Paul Fawcett Dong Sun Jingkai Gu research center for drug metabolism School of Life SciencesJilin UniversityChangchun 130012China State Key Laboratory of Supramolecular Structure and Materials Jilin UniversityChangchun 130012China Beijing Institute of drug metabolism Beijing 102209China

D-a-Tocopheryl polyethylene glycol 1000 succinate(TPGS,also known as vitamin E-TPGS)is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol(PEG)*** is approved by the US Food and drug Administration(FDA)and has found wide application in nanocarrier drug delivery systems(NDDS).Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based ***,to date,a bioassay for the simultaneous quantitation of TPGS and its metabolite,PEG1000,has not been *** the present study,we developed such an innovative bioassay and used it to investigate the pharmacokinetics,tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous *** addition,we evaluated the interaction of TPGS with cytochromes P450(CYP450s)in human liver *** results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that,after intravenous administration,TPGS and PEG1000 are mainly distributed to the spleen,liver,lung and kidney before both being slowly eliminated in urine and feces as *** vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of ***,our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.

关键词： TPGS LC-MS/MS Nanocarrier materials pharmacokinetics Tissue distribution metabolism Excretion Cytochrome P450