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Title Page

ABSTRACT

Contents

Abbreviations 17

1. INTRODUCTION 19

1.1. Lobeglitazone 19

1.2. Absorption, Distribution, Metabolism and Excretion 22

1.3. Metabolite Identification 26

1.4. Gender Differences 28

1.5. Objectives of the Study 29

2. MATERIALS AND METHODS 31

2.1. Chemicals and Reagents 31

2.2. Quantification of LB in Rat Plasma Using a Liquid-Chromatography/Tandem Mass Spectrometry 31

2.2.1. Liquid Chromatography Conditions 31

2.2.2. Mass Spectrometer Conditions 32

2.2.3. Sample Preparation by FF-PPT 33

2.2.4. Standards and Quality Control (QC) Samples 34

2.2.5. Method Validation 34

2.2.6. Application of the Assay 37

2.3. In vitro Absorption, Distribution and Elimination Studies 39

2.3.1. Parallel Artificial Membrane Permeability Assay (PAMPA) 39

2.3.2. Permeability Study in MDCK II Cells 40

2.3.3. Interaction of LB with Carrier-mediated Transports in MDCK Cells Expressing OATP1B1, OATP1B3, OAT1, OAT3, OCT2 and BCRP 42

2.3.4. Estimation of IC50 of LB on Digoxin Efflux in MDCKII Cells Expressing MDR1(이미지참조) 45

2.3.5. Determination of Plasma Protein Binding and the Blood-Plasma Partitioning of LB 46

2.3.6. Liver Microsomal Stability 48

2.3.7. Cytochrome P450 Inhibition Study 49

2.3.8. Metabolite Identification of LB 51

2.4. In vivo Pharmacokinetic Studies 55

2.4.1. Animals 55

2.4.2. Administration to Rats 55

2.4.3. Tissue Distribution Studies 57

2.4.4. Data Analysis 58

2.5. Gender Differences in the Hepatic Elimination and Pharmacokinetics of LB in Rats 58

2.5.1. Animals 58

2.5.2. LB Pharmacokinetic Studies 59

2.5.3. Stability of LB in Incubations Containing Male or Female Rat Liver Microsomes 60

2.5.4. Pharmacokinetic and Statistical Analyses 61

3. RESULTS 62

3.1. Quantification of LB in Rat Plasma Using a Liquid-Chromatography/ Tandem Mass Spectrometry 62

3.1.1. Chromatography 62

3.1.2. Specificity and Lower Limit of Quantification 63

3.1.3. Linearity 66

3.1.4. Accuracy, Precision, and Sample Dilution 66

3.1.5. Matrix Effect and Recovery 70

3.1.6. Stability 71

3.1.7. Applicability for Use in Pharmacokinetic Studies 77

3.2. In vitro Absorption, Distribution and Elimination Studies 80

3.2.1. PAMPA 80

3.2.2. Permeability Study with MDCKII Cells 80

3.2.3. Interaction of LB with SLC, MDR1 and BCRP Transporters 83

3.2.4. Standard PCR-based Cloning Strategy and the Interaction of LB with SLC, MDR1 and BCRP Transporters 87

3.2.5. Plasma Protein Binding and Blood-Plasma Partitioning of LB 98

3.2.6. Metabolic Stability of Liver Microsomes 98

3.2.7. Inhibition of Cytochrome P450 101

3.2.8. Metabolite Identification of LB in Rat Liver Microsomes 103

3.3. In vivo Pharmacokinetic Studies 113

3.3.1. Pharmacokinetic Study of Oral and Intravenous Administrations 113

3.3.2. Tissue Distribution 118

3.4. Gender Differences in the Hepatic Elimination and Pharmacokinetics of LB in Rats 121

3.4.1. Gender Difference in the Pharmacokinetics of LB in Rats 121

3.4.2. Differences in the Metabolic Stability of LB in Rat Hepatic Microsomes 124

4. DISCUSSION 125

5. REFERENCES 132

6. 국문초록 150

List of Tables

Table 1. Specificity of LB measurements in rat plasma. 68

Table 2. Calibration curves generated for LB in rat plasma. 69

Table 3. Summary of quality control samples for LB in rat plasma. 73

Table 4. Matrix effect, recovery, and precision for LB and... 74

Table 5. Stability of LB in stock solutions. 75

Table 6. Stability of quality control samples. 76

Table 7. Pharmacokinetic parameters of LB following an oral administration... 79

Table 8. Apparent permeability coefficients and efflux ratios for LB accros... 82

Table 9. List of cloning primer sequences. 96

Table 10. List of primer sequences for the confirmation of transporter gene... 97

Table 11. Percent inhibition on metabolism of substrate incubated with 10... 102

Table 12. Biotransformation of LB for predicted metabolites. 110

Table 13. Major MS/MS fragments of LB and its metabolites. 112

Table 14. Pharmacokinetic parameters of LB (a) after intravenous... 116

Table 15. Regression parameters and correlation coefficients for tissue... 120

Table 16. Summary of pharmacokinetic parameters of LB after ora... 123

List of Figures

Figure 1. The structures and product-ion scan spectra of (a) LB and (b)... 64

Figure 2. Multiple reaction monitoring (MRM) chromatography of (a) double... 65

Figure 3. Temporal profile of plasma concentration of LB in female rats... 78

Figure 4. Inhibitory effects of LB on the uptake of (a) estradiol-17β-... 85

Figure 5. Effects of inhibitors of LB on the cellular accumulation of digoxin... 86

Figure 6. Agarose gel electrophoresis of RT-PCR product using the primers... 93

Figure 7. Relative transport rate for MDCK cells expressing SLC transporters... 94

Figure 8. Metabolic stability profiles of LB in pooled rat liver microsomes. 100

Figure 9. Representative (a) total ion chromatogram and extracted ion... 107

Figure 10. Enhanced product ion spectra and proposed fragmentation... 108

Figure 11. Proposed metabolic pathways of LB incubated with rat liver... 109

Figure 12. Temporal profiles of plasma LB concentration in rats (a) after... 115

Figure 13. Tissue to plasma (T/P) concentration ratio of LB at 1 h after... 119

Figure 14. Mean plasma concentration-time profiles of LB after oral... 122

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