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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭錦樺(Ching-Hua Kuo) | |
dc.contributor.author | Divyabharathi Chepyala | en |
dc.contributor.author | 錢笛雅 | zh_TW |
dc.date.accessioned | 2021-07-11T15:26:42Z | - |
dc.date.available | 2019-03-11 | |
dc.date.copyright | 2019-03-11 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-10-16 | |
dc.identifier.citation | 1. Kataoka, H.; Lord, H., Chapter 23 Sampling and sample preparation for clinical and pharmaceutical analysis. 2002; Vol. 37, p 779-836.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78886 | - |
dc.description.abstract | The dried blood spot (DBS) sampling technique contains numerous advantages compared to the traditional plasma sampling technique. However, due to critical challenges, its applications in real world analysis except in relation to newborn screening are still minimal.
In this dissertation, we propose several approaches to mitigate the DBS associated challenges including low sensitivity and spotted blood volume to increase its applicability in pharmaceutical and metabolomics analysis. We first reported an ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry (UPLC-IB-QTOF) method for sensitive screening of abused drugs in DBS samples. An 80% acetonitrile solvent with a 5-min extraction by Geno grinder was used for sample extraction. A Poroshell column was used to provide efficient separation, and under optimal conditions, the analytical times were 15 and 5 min in positive and negative ionization modes, respectively. Ionization parameters of both electrospray ionization source and ion booster (IB) source containing an extra heated zone were optimized to achieve the best ionization efficiency of the investigated abused drugs. In spite of their structural diversity, most of the abused drugs showed an enhanced signal response with the high temperature ionization from an extra heated zone of IB source. Compared to electrospray ionization, the ion booster (IB) greatly improved the detection sensitivity for 86% of the analytes by 1.5 to 14-fold, and allowed the developed method to detect trace amounts of compounds on the DBS cards. The validation results showed that the coefficients of variation of intra-day and inter-day precision in terms of the signal intensity were lower than 19.65%. The extraction recovery of all analytes was between 67.21 and 119.38%. The limits of detection of all analytes were between 0.2 and 35.7 ng/mL. The stability study indicated that 7% of compounds showed poor stability (below 50%) on the DBS cards after 6 months of storage at room temperature and -80 °C. The reported method provides a new direction for abused drug screening using DBS. In order to improve the DBS applicability in drug monitoring, we developed a post column infused-internal standard (PCI-IS) combined with liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) method for the simultaneous quantification of 6 HIV medicines including tenofovir, emtricitabine, cobicistat, darunavir, ritonavir and elvitegravir for blood concentration estimation in DBS samples. Darunavir-d9 was selected as the PCI-IS for both blood estimation and drug quantification. Whole blood spots were extracted with 70% methanol for 10 min and compounds were separated by a T3 C18 column within 9.5 min with optimized gradient profile. The method was validated within the concentration range of 2.5–2500 ng/mL for all the drugs. The developed method fulfilled the FDA and EMA validation criteria. All the analytes were stable at the tested storage conditions except for cobicistat which degraded up to 25% in DBSs at room temperature within 7 days. Linear correlation coefficients between paired DBS and plasma sample concentrations were used to predict plasma concentrations from DBSs. Bland−Altman plots showed above 95% agreement between predicted plasma and measured plasma concentrations, confirming the suitability of DBSs for cART monitoring. DBS-based metabolomics analysis is a powerful tool for investigating new biomarkers for clinical use. To improve data quality for DBS-based metabolomics studies, we developed a PCI-IS assisted LC-ESI-MS/MS analysis method. An efficient sample preparation protocol with 80% acetonitrile as the extraction solvent was first established to improve the metabolite recovery. The PCI-IS assisted LC-ESI-MS method was used to simultaneously estimate the blood volume and correct the signal change caused by ion source contamination and the matrix effect to evaluate the spot volume effect and hematocrit (Hct) variation effect on target metabolites in DBSs. D8-phenylalanine was selected as the single PCI-IS to correct the matrix effect. For calibration of errors caused by the blood volume difference, 95% of the test metabolites showed good correlation between spot volume and signal intensity after PCI-IS correction. The spot volume was further calibrated by the same PCI-IS. Investigation of the Hct variation effect on target metabolites revealed that it affected the concentrations of metabolites in the DBS samples depending on their abundance in the red blood cell (RBC) or plasma; it is essential to pre-investigate the distribution of metabolites in blood to minimize the comparison bias in metabolomics studies. The PCI-IS-assisted strategy is anticipated to improve data quality for metabolomics studies using DBSs and benefit various clinical research applications. In conclusion, we demonstrated that UPLC-IB-QTOF and PCI-IS assisted LC-ESI-MS/MS analytical methods could solve the low sensitivity and spotted blood volume challenges of DBS sampling technique and could increase the it’s applicability in real world analysis. We anticipate that these developed methods could improve the simplicity and accuracy for forensic, pharmaceutical and meabolomics analysis and benefit precision medicine. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T15:26:42Z (GMT). No. of bitstreams: 1 ntu-107-F01423027-1.pdf: 8746148 bytes, checksum: 8cf6804ce5d7a769ba861488d8422672 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | Contents
ACKNOWLEDGEMENT II ABSTRACT III TABLE CONTENT IX FIGURE CONTENT X LIST OF ABBREVIATIONS XII CHAPTER 1 INTRODUCTION 1 1.1 Pharmaceutical and metabolomics analysis 2 1.2 Dried Blood Spot 2 1.2.1 DBS analysis methods 3 1.2.2 DBS clinical applications 4 1.2.3 Challenges associated with DBS sampling technique for clinical applications 6 1.3 Research aim of this dissertation 8 CHAPTER 2 SENSITIVE SCREENING OF ABUSED DRUGS IN DRIED BLOOD SAMPLES USING ULTRA-HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-ION BOOSTER-QUADRUPOLE TIME-OF-FLIGHT MASS SPECTROMETRY (UHPLC-IB-QTOF-MS) 10 2.1 Introduction 11 2.2 Experimental section 14 2.2.1 Standards and reagents 14 2.2.2 UHPLC-IB-QTOF-MS 15 2.2.3 Sample collection 15 2.2.4 Sample preparation 16 2.2.5 Validation 16 2.3 Results and discussion 18 2.3.1 Sample preparation method development 18 2.3.2 LC-QTOF-MS method development 19 2.3.3 Discussion 22 2.4 Conclusions 23 2.5 Tables 25 2.6 Figures 38 CHAPTER 3 SIMULTANEOUS QUANTIFICATION OF 6 HIV MEDICINES ON DRIED BLOOD SPOTS BY POSTCOLUMN INFUSED-INTERNAL STANDARD METHOD COMBINED WITH LC-ESI-MS 43 3.1 Introduction 44 3.2 Experimental section 46 3.2.1 Chemicals and Materials 46 3.2.2 UHPLC-ESI-MS system 47 3.2.3 Preparation of stock and quality control samples 48 3.2.4 DBS sample preparation 49 3.2.5 Plasma sample preparation 49 3.2.6 PCI-IS for blood volume estimation on DBS cards and for drug quantification 49 3.2.7 Method validation 50 3.2.8 Clinical Sample Collection 52 3.2.9 Data and Statistical Analysis 52 3.3 Results and discussion 53 3.3.1 Optimization of Analytical method 53 3.3.2 Selection of PCI-IS and its utility for both blood volume estimation and correction and for drug quantification 55 3.3.3 Method validation 56 3.3.4 Correlation between the quantification results of DBSs and plasma sampling 57 3.4 Conclusions 59 3.5 Tables 60 Table 3.5.1. Mass parameters, retention time and chemical structures of the target compounds 60 3.6 Figures 69 CHAPTER 4 AN IMPROVED DBS-BASED METABOLOMICS ANALYSIS BY POST COLUMN INFUSED-INTERNAL STANDARD ASSISTED LIQUID CHROMATOGRAPHY-ELECTROSPRAY IONIZATION MASS SPECTROMETRY METHOD 75 4.1 Introduction 76 4.2 Experimental section 78 4.2.1 Chemicals and materials 78 4.2.2 PCI-IS assisted LC-ESI-MS analysis 79 4.2.3 Metabolomic profiling 80 4.2.4 DBS sample preparation procedure 80 4.2.5 PCI-IS method for the estimation of blood volume on DBS cards and matrix effect correction 81 4.2.6 Preparation of DBS sample for evaluation of Hct variation effect 82 4.2.7 Data analysis 82 4.3 Results and discussion 83 4.3.1 Method optimization 84 4.3.2 Using the PCI-IS to minimize the lipid accumulation effect on method robustness 85 4.3.3 Using the PCI-IS method to estimate the blood volume and calibrate Blood volume difference caused errors 87 4.3.4 Evaluation of Hct variation effect on target metabolites 88 4.4 Conclusions 91 4.6 Figures 94 CHAPTER 5 SUMMARY AND PERSPECTIVE 101 5.1 Summary and Perspective 102 CHAPTER 6 REFERENCES 104 PUBLICATION LIST 114 Table content Table 2.5.1. LC–MS/MS parameters for the abused drugs and their metabolites. 25 Table 2.5.2. Validation results of abused drugs and metabolites including LOD, intra-day (n=9) and inter-day (n=9) precision. 29 Table 2.5. 3. Validation results of abused drugs and metabolites including extraction recovery (n=9), matrix effect (n=9) and stability (n=6). 33 Table 3.5.1. Mass parameters, retention time and chemical structures of the target compounds 60 Table 3.5.2. Selection of PCI-IS by evaluating the quantification accuracy and precision using calibration curve generated with five different isotope labelled internal standards as PCI-IS (n=30). 62 Table 3.5.3. Blood volume estimation accuracy of the PCI-IS method. 64 Table 3.5.4. Calibration curve, limit of detection (LOD) and limit of quantification (LOQ) of AR drugs in DBS samples. 64 Table 3.5.5. Intra-day, inter-day precision and accuracy, extraction recovery (ER) and matrix effect (ME) of all drugs.a 65 Table 3.5.6. Stability of 6 AR drugs at different conditions. (A) Stability of 6 AR drugs in whole blood samples at room temperature (RT) for 2 and 4 hours and at 4 oC for 24 and 48 hours. (B) Short-term and long-term stability of 6 AR drugs in DBS samples stored at RT, 4 oC and -20 oC for 1, 7 and 30 days. (C) Post preparation stability of 6 AR drugs stored at 4 oC in auto sampler for 48 hours and at -20 oC for 1 week. All the conditions were set according to the sample collection and analysis. 66 Table 4.5.1. Mass parameters, MRM transitions and metabolomics pathways of targeted metabolites. 92 Table 4.5.2. Extraction efficiency and repeatability of six extraction solvents evaluated by untargeted metabolomics analysis. 93 Figure content Figure 2.6.1 Extraction recoveries of 57 abused drugs obtained by different extraction solvents (n=9). The spiking concentration for all the abused drugs was 2 µg/mL. 38 Figure 2.6.2 Extraction recoveries of 57 abused drugs obtained from 1, 3 and 5 mins of extraction by Geno grinder (n=9). The spiking concentration for all the abused drugs was 2 µg/mL. 39 Figure 2.6.3 Extraction ion chromatograms of DBS samples obtained under optimized conditions in A) positive and B) negative ionization mode. The spiking concentration for all the abused drugs was 0.2 µg/mL. Peak number was given by compound retention time from positive and negative separation modes. 40 Figure 2.6.4 Comparison of signal intensities obtained by ESI and IB. Spiking concentration for all the abused drugs was 0.2 µg/mL. ESI parameters: endplate offset voltage 500 V, capillary voltage 4500 V (positive ionization mode), 3000 V (negative ionization mode), dry gas flow 12 L/min, dry temperature 250 °C, nebulizer gas 36 psi. IB parameters: end plate offset voltage 400 V, charging voltage 300 V, capillary voltage 1000 V, dry gas flow 4 L min-1, nebulizer flow 60 psi, dry temperature 200 °C, vaporizer temperature 150 °C and sheath gas flow 150 L/hr. Tuning parameters including hexapole RF 100 Vpp, collision RF 700 Vpp, transfer time 40 µs, and pre-pulse storage 10 µs were the same for both the ESI and IB sources. 41 Figure 2.6.5 Effect of vaporizer temperature (VT) in the IB on signal improvement. Values are shown as analyte response (PA) normalized to the results obtained from VT 150. The spiking concentration for all the abused drugs was 0.2 µg/mL. 42 Figure 3.6.1 Concept of blood volume estimation by PCI-IS. (Modified from ref 27) 69 Figure 3.6.2 Schematic representation of the study design. 70 Figure 3.6. 3 MRM Chromatograms of (A) tenofovir, (B) emtricitabine , (C) cobicistat, (D) darunavir, (E) ritonavir and (F) elvitegravir from DBS sample obtained under optimal LC-MS/MS conditions. The concentration of all the drugs including TFV/FTC/COBI/DRV/RTV/EVG were 2.5/5/5/10/10/20 ng/mL 71 Figure 3.6.4 Calibration curve of for estimation of the blood volume on the DBS card by using blood volume and reciprocal PCI-IS intensity. 72 Figure 3.6.5 correlation between paired DBS and plasma samples for (A) tenofovir (TFV) (B) emtricitabine (FTC) (C) cobicistat (COBI) (D) darunavir (DRV) (E) ritonavir (RTV) and (F) elvitegravir (EVG). 73 Figure 3.6. 6 The Bland-Altman plots for the predicted plasma concentrations for (A) tenofovir (TFV) (B) emtricitabine (FTC) (C) cobicistat (COBI) (D) darunavir (DRV) (E) ritonavir (RTV) and (F) elvitegravir (EVG) with the measured plasma concentrations. The mean (blue line), the upper and lower LoAs (95% CI, dashed redlines) are also indicated. 74 Figure 4.6.1 Schematic representation of the study design. A) Sample extraction optimization during untargeted metabolomics analysis using LC-QTOF. B) PCI-IS strategy for blood volume estimation of samples on DBS cards and calibration of blood volume difference-caused errors. C) Evaluation of Hct variation effect on target metabolites. 94 Figure 4.6.2 The overlaid total ion chromatograms of DBS (green color) and plasma (red color) samples obtained from precursor ion scan m/z 184. 95 Figure 4.6.3 Effect of Hybrid SPE on the extraction recoveries of the target metabolites. 96 Figure 4.6.4 Effect of the PCI-IS on improving method robustness evaluated by comparing the relative standard deviation of target metabolites obtained by 50 continuous analyses of the same DBS extract. 97 Figure 4.6.5 Calibration curve of blood volume and reciprocal PCI-IS intensity for the estimation of the blood volume on the DBS card. 98 Figure 4.6.6 Normalized signal intensity of metabolites obtained by different blood volume calculated (A) with and (B) without PCI-IS calibration. 99 Figure 4.6.7 Evaluation of the Hct variation effect on target metabolites. 100 | |
dc.language.iso | en | |
dc.title | 以液相層析質譜儀開發藥物與代謝體於採血卡
之分析方法 | zh_TW |
dc.title | Development of liquid chromatography-mass
spectrometry methods for pharmaceutical and metabolomics analysis using dried blood spot | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 李仁愛(Jen-Ai Lee),陳家揚(Chia-Yang Chen),陳逸然(Yet-Ran Chen),傅明仁(Ming-Ren Fuh) | |
dc.subject.keyword | 採血卡,濫用藥物,離子加壓器,抗愛滋病藥物,柱後輸注內標,血液體積,血比溶,採血卡上之代謝體研究, | zh_TW |
dc.subject.keyword | Dried blood spot,drug abuse,ion-booster,anti-HIV drugs,post column infused internal standard,blood volume,Hematocrit effect,DBS-based metabolomics, | en |
dc.relation.page | 114 | |
dc.identifier.doi | 10.6342/NTU201804215 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-10-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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