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Contents

Part I. Distribution and Metabolism of New ALK-5 inhibitor, IN-1130 13

ABSTRACT 14

I. Introduction 16

A. Drug metabolism in drug development 16

1. Phase I and phase II metabolism 16

2. Cytochrome P450s in drug metabolism 17

3. Flavin-containing monooxygenase (FMO) 18

4. Approches to identify drug metabolizing enzymes 18

B. IN-1130 as activin receptor like kinase-5 (ALK5) inhibitor 20

C. Objectives of study 25

II. Materials and methods 26

A. Materials 26

B. Animals 26

C. Tissue distribution study of IN-1130 26

D. Tissue distribution study of IN-1233 28

E. Isolated rat liver perfusion assay 28

F. Preparation of microsome 28

G. In vitro metabolism of IN-1130 and IN-1233 29

1. Assay of CYP-mediated metabolism. 29

2. CYP enzyme inhibition assays. 29

3. Assay of flavin-containing monooxygenase(FMO)-mediated metabolism. 29

4 . Enzyme digestion of glucuronide and sulfate conjugates. 30

H. HPLC Analysis 30

I. LC/MS analysis 30

J. NMR analysis of IN-1130 and its metabolite 31

K. Statistical analysis 31

III. Results 32

A. Tissue distribution of IN-1130 32

1. Plasma concentration of IN-1130 following oral administration to mice and rats 32

2. Tissue distribution of IN-1130 36

3. Disposition of metabolite M1 42

B. Metabolism of IN-1130 45

1. Metabolism of IN-1130 in isolated rat liver perfusion system 45

2. Metabolism of low concentration of IN-1130 in vitro 49

3. Role of flavin-containing monooxygenases (FMOs) in metabolism of IN-1130 51

4. Role of CYPs in metabolism of IN-1130 65

5. Role of phase II metabolizing enzymes in metabolism of IN-1130 80

6. Characterization of metabolites of IN-1130 83

C. Disposition of IN-1233 89

1. Mean tissue and plasma concentration of IN-1233 in mouse 89

2. Relative peak area of IN-1233 and its metabolites in mouse 90

3. Identification of specific CYP and FMO isozymes metabolizing IN-1233 93

IV. Discussion 100

REFERENCES 106

국문 요약 114

Part II. Toxicity of Novel Paclitaxel Solubilizer, Aceporol 330 116

ABSTRACT 117

I. Introduction 118

II. Materials and methods 120

A. Materials 120

B. Animals 120

C. Single dose toxicity study in mice 122

D. 2-Week repeated dose toxicity study in mice 122

E. Single dose toxicity study in beagle dogs 123

F. 2-Week repeated dose toxicity study in beagle dogs 123

G. Hematological investigation and blood chemistry analysis 124

H. Autopsy study 125

I. Histopathological study 125

J. Statistical analysis 125

III. Results 126

A. Single dose toxicity study in mice 126

B. 2-Week repeated dose toxicity study in mice 129

C. Single dose toxicity study in beagle dogs 135

D. 2-Week repeated dose toxicity study in beagle dogs 135

IV. Discussion 145

REFERENCES 148

국문 요약 151

감사의 글 152

LIST OF TABLES

Table 1. Tissue-to-plasma ratio of IN-1130 in rodents after oral administration α(이미지참조) 41

Table 2. CYP metabolism of low concentration of IN-1130 in liver microsome 50

Table 3. Metabolism of IN-1130 by liver microsome (pH 9.5) 57

Table 4. Metabolism of IN-1130 by supersomal FMOs 61

Table 5. Effects of CYP inhibitors on the metabolism of IN-1130 in human and mice liver microsomes (pH 9.5) 63

Table 6. Metabolism of IN-1130 in liver microsomes of monkey and dog 70

Table 7. Metabolism of IN-1130 by supersomal CYPs. 74

Table 8. LC-MS/MS analysis of IN-1130 and its metabolites. 86

Table 9. Metabolism of IN-1233 by supersomal CYPs and FMOs. 95

Table 10. Mortality of solubilizer in mouse single dose toxicity test 127

Table 11. Body weight changes of mouse in single dose toxicity test 128

Table 12. Body weight changes of mouse in 2-week repeated dose toxicity test 130

Table 13. Organ weight of mouse after 2-week repeated dose toxicity test 131

Table 14. Hematological test for mouse after 2-week repeated dose toxicity test 132

Table 15. Blood chemistry analysis of mouse after 2-week repeated dose toxicity test 133

Table 16. Body weight changes of beagle dog in single dose toxicity test 137

Table 17. Body weight changes of beagle dog in 2-week repeated dose toxicity test 138

Table 18. Food consumption of beagle dog in 2-week repeated dose toxicity test 139

Table 19. Water consumption of beagle dog in 2-week repeated dose toxicity test 140

Table 20. Organ weight of beagle dog after 2-week repeated dose toxicity test 141

Table 21. Hematological test for beagle dog after 2-week repeated dose toxicity test 142

Table 22. Blood chemistry analysis of beagle dog after 2-week repeated dose toxicity test 143

LIST OF FIGURES

Figure 1. Structures of ALK5 inhibitors 27

Figure 2. Mean plasma concentration-time curve of IN-1130 in mice. 34

Figure 3. Mean plasma concentration-time curve of IN-1130 in rats. 35

Figure 4. Tissue distribution of IN-1130 in mice following oral administration. 39

Figure 5. Tissue distribution of IN-1130 in rats following oral administration. 40

Figure 6. Tissue distribution of a major IN-1130 metabolite (M1) in mice following oral administration of IN-1130. 43

Figure 7. Tissue distribution of a major IN-1130 metabolite (M1) in rats following oral administration of IN-1130. 44

Figure 8. Metabolism of IN-1130 in isolated rat liver perfusion system. 47

Figure 9. Amount of IN-1130 and its metabolite in perfused rat liver. 48

Figure 10. Effect of methimazole on the metabolism of IN-1130 in isolated rat liver perfusion system. 53

Figure 11. Effect of methimazole on the concentration of IN-1130 in perfused rat liver. 54

Figure 12. Metabolism of IN-1130 in human, mouse, rat, dog and monkey liver microsomes (pH 9.5). 58

Figure 13. Comparison of HPLC profile of IN-1130 metabolite by rat kidney and liver microsome. 59

Figure 14. Role of FMO on the metabolism of IN-1130 in rat liver microsomes. 62

Figure 15. Effects of CYP inhibitors on the metabolism of IN-1130 in human, mice and rat liver microsomes (pH 9.5). 64

Figure 16. Metabolism of IN-1130 in mouse liver microsomes. 67

Figure 17. Metabolism of IN-1130 in rat liver microsomes. 68

Figure 18. Metabolism of IN-1130 in human liver microsomes. 69

Figure 19. Cytochrome P450 mediated metabolism of IN-1130 in human, mouse, rat, dog and monkey liver microsomes. 71

Figure 20. Human CYP2C8 specific metabolism of IN-1130. 75

Figure 21. Human CYP2C19 specific metabolism of IN-1130. 76

Figure 22. Human CYP2D6 specific metabolism of IN-1130. 77

Figure 23. Human CYP3A4 specific metabolism of IN-1130. 78

Figure 24. Effect of CYP isozyme-specific inhibitors on the metabolism of IN-1130 by human liver microsome. 81

Figure 25. Effect of glutathione S-transferase (GST) and UDP-glucuronyltransferases (UDPGT) on metabolism of IN-1130. 82

Figure 26. LC-MS/MS spectra of IN-1130 (A) and its major metabolite, M1 (B). 87

Figure 27. ¹H-NMR spectra of IN-1130 (A) and its metabolite, M1 (B). 88

Figure 28. Tissue distribution of IN-1233 following oral administration to mice. 91

Figure 29. Tissue distribution of major IN-1233 metabolite (M1; m/z 421) in mice following oral administration of IN-1233. 92

Figure 30. Human CY2C8 specific metabolism of IN-1233. 96

Figure 31. Human CYP2C19 specific metabolism of IN-1233. 97

Figure 32. Human CYP2D6 specific metabolism of IN-1233. 98

Figure 33. Human CYP3A4 specific metabolism of IN-1233. 99

Figure 34. Chemical structure of solubilizer 121

LIST OF SCHEMES

Scheme 1. TGF-β and tissue fibrosis (Verrecchia and Mauviel, 2007) 21

Scheme 2. The transforming growth factor-β (TGF- β)/SMAD pathway. 22

Scheme 3. Examples of TGF-β inhibitors α(이미지참조) 23

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