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Journal of Pharmaceutical Analysis 2023年第6期13卷 683-688页

作者： Dong Sun Chunyu Wang Yanxia Fan jingkai gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun130012China State Key Laboratory of Supramolecular Structure and Materials Jilin UniversityChangchun130012China Beijing Institute of Drug Metabolism Beijing102209China Jilin Institute for Drug Control Changchun130033China

During the analysis of benziamidazole-class irreversible proton pump inhibitors,an unusual mass spectral response with the mass-to-charge ratio at[Mt10]t intrigued us,as it couldn't be assigned to any literature known relevant structure,intermediate or adduct ***,this mysterious mass pattern of[Mt10]t has been gradually observed by series of marketed proton pump inhibitors,***,pantoprazole,lansoprazole and *** the previous attempts to isolate the corresponding component were *** investigation of present work addresses this kind of signal to a pyridinium thiocyanate mass spectral intermediate(10),which is the common fragment ion of series of labile *** origin of such aggregates can be traced to the reactive intermediates formed by acid-promoted *** reactive intermediates tend to react with each other and give raise series of complicated aggregates systematically in a water/acetonitrile solution by electrospray *** structure of the corresponding pyridinium thiocyanate species of omeprazole(10a)has been eventually characterized with the help of synthetic specimen(10a′).Our structural proposal as well as its origin was supported by in situ nuclear magnetic resonance,chemical derivatization and colorimetric experiments.

关键词： Proton pump inhibitor Mass spectrometry Electrospray ionization Pseudo-molecular ion Pyridinium thiocyanate

Current status of in vivo bioanalysis of nano drug delivery systems

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Journal of Pharmaceutical Analysis 2020年第3期10卷 221-232页

作者： Tingting Wang Di Zhang Dong Sun jingkai gu Clinical Laboratory The First HospitalJilin UniversityChangchun130061PR China Research Institute of Translational Medicine The First HospitalJilin UniversityChangchun130061PR China Research Center for Drug Metabolism College of Life ScienceJilin UniversityChangchun130012PR China Department of Biopharmacy College of Life ScienceJilin UniversityChangchun130012PR China Key Laboratory of Molecular Pharmacology and Drug Evaluation Ministry of EducationYantai UniversityYantai264005PR China

The development of nano drug delivery systems(NDDSs)provides new approaches to fighting against *** NDDSs are specially designed to serve as carriers for the delivery of active pharmaceutical ingredients(APIs)to their target sites,which would certainly extend the benefit of their unique physicochemical characteristics,such as prolonged circulation time,improved targeting and avoiding of *** the remarkable progress achieved over the last three decades,the understanding of the relationships between the in vivo pharmacokinetics of NDDSs and their safety profiles is *** of NDDSs is far more complicated than the monitoring of small molecular drugs in terms of structure,composition and aggregation state,whereby almost all of the conventional techniques are inadequate for accurate profiling their pharmacokinetic behavior in ***,the advanced bioanalysis for tracing the in vivo fate of NDDSs is summarized,including liquid chromatography tandemmass spectrometry(LC-MS/MS),Forster resonance energy transfer(FRET),aggregation-caused quenching(ACQ)fluorophore,aggregation-induced emission(AIE)fluorophores,enzyme-linked immunosorbent assay(ELISA),magnetic resonance imaging(MRI),radiolabeling,fluorescence spectroscopy,laser ablation inductively coupled plasma MS(LA-ICP-MS),and size-exclusion chromatography(SEC).Based on these technologies,a comprehensive survey of monitoring the dynamic changes of NDDSs in structure,composition and existing form in system(*** polymers,released and encapsulated drug)with recent progress is *** hope that this review will be helpful in appropriate application methodology for investigating the pharmacokinetics and evaluating the efficacy and safety profiles of NDDSs.

关键词： NDDSs Polymer Methodology Pharmacokinetics Release

Analytical methods for investigating in vivo fate of nanoliposomes:A review

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Journal of Pharmaceutical Analysis 2018年第4期8卷 219-225页

作者： Chong Su Yingze Liu Yang He jingkai gu College of Life Science Jilin University Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of lowa

Nanoliposomes are considered to be the most successful nanoparticle drug delivery system, but their fate in vivo has not been fully understood due to lack of reliable bioanalytical methods, which seriously limits the development of liposomal drugs. Hence, an overview of currently used bioanalytical methods is imperative to lay the groundwork for the need of developing a bioanalytical method for liposome measurements in vivo. Currently, major analytical methods for nanoliposomes measurement in vivo include fluorescence labeling, radiolabeling, magnetic resonance imaging（MRI）, mass spectrometry and computed tomography. In this review, these bioanalytical methods are summarized, and the advantages and disadvantages of each are discussed. We provide insights into the applicability and limitations of these analytical methods in the application of nanoliposomes measurement in vivo, and highlight the recent development of instrumental analysis techniques. The review is devoted to providing a comprehensive overview of the investigation of nanoliposomes design and associated fate in vivo, promoting the development of bioanalytical techniques for nanoliposomes measurement, and understanding the pharmacokinetic behavior, effectiveness and potential toxicity of nanoliposomes in vivo.

关键词： Liposomes Analytical methods In vivo fate Liposomal drug

Liquid chromatography–tandem mass spectrometry method for simultaneous determination of valproic acid and its ene-metabolites in epilepsy patient plasma

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Journal of Pharmaceutical Analysis 2016年第2期6卷 112-116页

作者： Huan Lu Chong Su Lei Yin Liqiang gu jingkai gu Xiaohui Chen School of Pharmacy Shenyang Pharmaceutical University Research Center for Drug Metabolism College of Life ScienceJilin University Clinical Pharmacology Center Research Institute of Translational Medicine the First Hospital of Jilin University

A simple and high throughput method was developed and validated for simultaneous determination of valproic acid and its two toxicant ene-metabolites, 2-enevalproic acid and 4-enevalproic acid in epilepsy patient plasma using liquid chromatography-tandem mass spectrometry. Probenecid was used as in- ternal standard and solid-phase extraction was selected for sample preparation. A chromatographic separation was performed on an Agilent Poroshell SB-C18 column （50 mm × 4.6 mm i.d., 2.7μm） by an optimized gradient elution at a flow rate of 0.9 mL/min. The total run time was 7 rain. Electrospray ionization was used in negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 143.0→143.0 for valproic acid, m/z 140.9 →140.9 for 2-enevalproic acid and 4-enevalproic acid for their poor fragments, and m/z 283.9→239,9 for probenecid. The results showed good linearity ofvalproic acid, 2-enevalproic acid and 4-enevalproic acid in their respective linear ranges. The correlation coefficients were more than 0.998, The intra- and inter-day precision of the assay was less than 11.0% and the accuracy ranged from 2% to 12%. This analytical method was successfully applied to assay plasma concentrations of valproic acid and its two ene-metabolites in epilepsy patient plasma and used for therapeutic drug monitoring.

关键词： Liquid chromatography-tandem massspectrometry Valproic acid 2-enevalproic acid 4-enevalproic acid

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

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

纳米药物递送系统体内命运分析新方法与新技术研究进展

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药学进展 2024年第10期48卷 747-760页

作者：王心怡付淑军孟祥骏吴伟顾景凯天津大学医学部药物科学与技术学院吉林大学超分子结构与材料国家重点实验室超分子化学生物学研究中心生命科学学院药物代谢研究中心国家药品监督管理局药品审评中心复旦大学药学院

纳米药物递送系统（NDDSs）能够改善药物的药代动力学行为，将活性药物成分靶向递送至病灶，并控制药物释放。近年来，随着纳米技术的快速发展，NDDSs在医药领域展现出巨大潜力，已成为该领域的研究热点。对NDDSs的体内命运进行精准分... 详细信息

纳米药物递送系统（NDDSs）能够改善药物的药代动力学行为，将活性药物成分靶向递送至病灶，并控制药物释放。近年来，随着纳米技术的快速发展，NDDSs在医药领域展现出巨大潜力，已成为该领域的研究热点。对NDDSs的体内命运进行精准分析，是揭示其复杂体内过程，实现纳米药物安全、有效递送的关键之一。NDDSs在体内包含负载型药物、游离型药物、纳米载体和载体材料等多种形态成分，在复杂的生命体系中全面精准分析这些成分的动态变化具有极高的技术挑战。受分析方法与分析技术的制约，目前对于NDDSs的体内命运研究仍存在许多挑战，极大阻碍了NDDSs的快速发展与临床转化。综述对NDDSs中游离型药物、负载型药物、纳米载体和纳米材料的分析新方法、新技术及其在纳米药代动力学中的应用进行介绍，并对该领域未来研究方向提出展望，以期为NDDSs的体内命运相关研究提供参考。

关键词：纳米药物递送系统纳米载体体内命运生物分析新方法与新技术

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

Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols(PEGs) with particular reference to P-glycoprotein

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Acta Pharmaceutica Sinica B 2020年第10期10卷 2002-2009页

作者： Tingting Wang Yingjie guo Yang He Tianming Ren Lei Yin John Paul Fawcett jingkai gu Huimin Sun Clinical Laboratory First HospitalJilin UniversityChangchun 130061China Research Institute of Translational Medicine First HospitalJilin UniversityChangchun 130061China Research Center for Drug Metabolism College of Life ScienceJilin UniversityChangchun 130012China Department of Pharmaceutical Sciences and Experimental Therapeutics College of PharmacyUniversity of IowaIowa City IA 52242USA Beijing Institute of Drug Metabolism Beijing 102209China National Institutes for Food and Drug Control Beijing 100050China

Polyethylene glycols(PEGs)in general use are polydisperse molecules with molecular weight(MW)distributed around an average value applied in their designation e.g.,PEG *** research has shown that PEGs can act as P-glycoprotein(P-gp)inhibitors with the potential to affect the absorption and efflux of concomitantly administered ***,questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been *** this study,we examined the mechanism of uptake of PEGs by MDCK-mock cells,in particular,the effect of MW and interaction with P-gp by MDCK-hMDRl and A549 *** results show that:(a)the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors;(b)PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil;and(c)uptake of PEGs of low MW(5000 Da)occurs by a combination of passive diffusion and caveolae-mediated *** findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.

关键词： P-gp PEGs P-gp-substrate Passive diffusion Endocytosis

Separation and simultaneous quantitation of PGF2α and its epimer 8-iso-PGF2α using modifier-assisted differential mobility spectrometry tandem mass spectrometry

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Acta Pharmaceutica Sinica B 2018年第2期8卷 228-234页

作者： Chunsu Liang Hui Sun Xiangjun Meng Lei Yina J.Paul Fawcett Huaidong Yu Ting Liu jingkai gu Research Center for Drug Metabolism School of Life Sciences Jilin University School of Pharmacy University of Otago Shanghai AB Sciex Analytical Instrument Trading Co. Ltd.

Because many therapeutic agents are contaminated by epimeric impurities or form epimers as a result of metabolism, analytical tools capable of determining epimers are increasingly in demand. This article is a proof-of-principle report of a novel DMS–MS/MS method to separate and simultaneously quantify epimers, taking PGF2α and its 8-epimer, 8-iso-PGF2α, as an example. Good accuracy and precision were achieved in the range of 10–500 ng/m L with a run time of only 1.5 min. Isopropanol as organic modifier facilitated a good combination of sensitivity and separation. The method is the first example of the quantitation of epimers without chromatographic separation.

关键词： Differential mobility spectrometry Mass spectrometry Epimer PGF2α 8-iso-PGF2α