아주대학교

목차

1. Introduction 1
2. Materials and methods 7
A. Materials 7
B. Animals 7
C. Induction of various diseases in rats 8
D. Biochemical profiles and tissue microscopy 9
E. Rat plasma protein binding of tofacitinib 9
F. Intravenous and oral administration of tofacitinib in rats 10
G. Measurement of Vmax, Km, and CLint 11
H. Immunoblot analysis 11
I. HPLC analysis 12
J. Pharmacokinetic analysis 12
K. Statistical analysis 13
3. Results 14
A. Acute kidney injury 14
1. Preliminary data and tissue microscopy 14
2. Plasma protein binding of tofacitinib 15
3. Pharmacokinetics of tofacitinib after it intravenous and oral administration to rats 18
4. In vitro metabolism of tofacitinib 24
5. Expression of CYP isozymes 26
B. Acute liver injury 28
1. Preliminary data and tissue microscopy 28
2. Plasma protein binding of tofacitinib 29
3. Intravenous and oral administration of tofacitinib in rats 32
4. In vitro metabolism of tofacitinib 37
5. Expression of CYP isozymes 39
C. Diabetes mellitus 41
1. Preliminary data and tissue microscopy 41
2. Plasma protein binding of tofacitinib 42
3. Intravenous and oral administration of tofacitinib in rats 45
4. In vitro metabolism of tofacitinib 49
5. Expression of CYP isozymes 51
D. PBPK simulation 53
1. Physicochemical properties of tofacitinib 53
2. PBPK model structure for population with various diseases 55
3. Rats to human using single species extrapolation method 57
4. Kidney injury model 59
5. Liver injury model 63
6. Diabetes mellitus model 67
4. Discussion 71
5. Conclusion 84
6. Reference 85
KOREAN ABSTRACT 100