Effects of natural components on the pharmacokinetics of tofacitinib and PBPK simulation in various diseases
- 주제(키워드) tofacitinib , pharmacokinetics , disease model , natural components , PBPK simulation
- 주제(DDC) 615.1
- 발행기관 아주대학교 일반대학원
- 지도교수 김소희
- 발행년도 2025
- 학위수여년월 2025. 2
- 학위명 박사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000034293
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib, an inhibitor of Janus kinase 1 and 3, is prescribed for the treatment of rheumatoid arthritis. Its metabolism primarily occurs in the liver through the action of cytochrome P450 enzymes, specifically CYP3A1/2 and CYP2C11. Various diseases affecting the liver and kidneys could alter tofacitinib’s pharmacokinetics, as it undergoes metabolism in the liver. To prevent acute kidney injury, acute liver injury, and diabetes mellitus, natural compounds will be administered, and their protective effects on liver and kidney function will be evaluated. Additionally, the pharmacokinetic parameters of tofacitinib will be assessed, and a physiologically based pharmacokinetic (PBPK) simulation will be conducted based on the clearance data obtained from rats. The pharmacokinetic parameters of tofacitinib were assessed after administering loganin (LGN) to rats with cisplatin-induced acute kidney injury (AKI). The protective effects of resveratrol (RVT) and its pharmacokinetic alterations were evaluated in acetaminophen-induced acute liver injury (ALI). We investigated the effects of isosakuranetin (ISN) on the pharmacokinetics in rats with streptozotocin-induced diabetes mellitus (STZ). PBPK simulation was conducted using PK-Sim and Simcyp to predict the pharmacokinetics of tofacitinib in patients with kidney injury, liver injury, and diabetes mellitus. We observed improvements in liver, kidney function, and blood glucose levels in each disease model after administering the natural components. The AUC also decreased, nearing values of the control rats. The predicted human pharmacokinetic parameters of tofacitinib from the PBPK simulation closely matched clinical data. These findings offer valuable insights for optimizing tofacitinib dosing in patients with specific diseases. Key words: tofacitinib, pharmacokinetics, disease model, natural components, PBPK simulation
more목차
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
