Protective effects of resveratrol on the pharmacokinetics of tofacitinib in rats with cisplatin-induced acute renal failure
- 주제(키워드) tofacitinib , resveratrol , acute renal failure , pharmacokinetics , renal protective effect
- 주제(DDC) 651.1
- 발행기관 아주대학교 일반대학원
- 지도교수 김소희
- 발행년도 2024
- 학위수여년월 2024. 2
- 학위명 석사
- 학과 및 전공 일반대학원 바이오헬스규제과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000033612
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib, a JAK inhibitor commonly used to treat rheumatoid arthritis (RA), may result in renal involvement in RA patients due to chronic inflammation and drug toxicity. Tofacitinib undergoes 70% metabolism in the liver and 30% excretion via the kidneys. The area under the curve (AUC) of tofacitinib could elevate with the severity of renal disease, potentially leading to drug toxicity. Resveratrol, a natural polyphenolic substance in red grapes and wine, acts as a SIRT1 activator and antioxidant. It plays a role in preventing renal injury by reducing oxidative stress, inhibiting inflammation, and decreasing p53 acetylation, apoptosis, and cytotoxicity. This study investigated the pharmacokinetic changes of tofacitinib when administered with resveratrol in a rat model of cisplatin-induced acute renal failure (ARF). In vitro studies indicated a reduced expression of CYP3A1/2 and CYP2C11 in hepatic microsomes and decreased enzyme activity in hepatic and intestinal microsomes within the ARF group. Pharmacokinetic analysis revealed decreased clearance (CL), renal clearance (CLR), and non-renal clearance (CLNR). The renal injury observed in the ARF group led to diminished metabolism and excretion of tofacitinib, subsequently resulting in elevated plasma concentrations. In comparison to the CON group, intravenous and oral administration in the ARF group showed induction in the AUC, with an increase of 190% and 103%, respectively. Preliminary results indicate decreased Blood Urea Nitrogen (BUN) and Serum Creatinine (SCR), along with an increased Creatinine Clearance (CLCR) in rats experiencing acute renal failure pretreated with resveratrol (AR). In vitro studies indicated an increased expression of CYP3A1/2 and CYP2C11 in hepatic microsomes, along with increased enzyme activity in hepatic and intestinal microsomes in the AR group. Pharmacokinetic analysis revealed that CL, CLR, and CLNR were restored in the AR group. Resveratrol pretreatment mitigated renal dysfunction, consequently restoring the metabolism and excretion of tofacitinib. This resulted in lower plasma concentrations of tofacitinib and subsequently decreased AUC. In comparison to the ARF group, the AUC in the AR group decreased by 49.2% for intravenous administration and by 38.2% for oral administration.
more목차
I. INTRODUCTION 1
II. METHOD 4
A. Chemicals 4
B. Animal and maintenance 4
C. Treatments in rats 4
D. Preliminary study 5
E. Intravenous and oral administration of tofacitinib 5
F. HPLC analysis of tofacitinib 6
G. Pharmacokinetics analysis 7
H. In vitro metabolism of tofacitinib in the hepatic and intestinal microsome 7
I. Immunoblot analysis 8
J. Statistical analysis 8
III. RESULTS 9
A. Preliminary study 9
B. Pharmacokinetics of tofacitinib after intravenous administration 12
C. Pharmacokinetics of tofacitinib after oral administration 15
D. In vitro metabolism of tofacitinib in the hepatic and intestinal microsome 18
E. Protein expression of CYP 450 isozymes and P-gp 20
IV. DISCUSSION 22
V. CONCLUSION 25
REFERENCES 26
KOREAN ABSTRACT 29
