Streptozotocin으로 유도된 당뇨 모델에서의 tofacitinib의 약동학적 변화
Pharmacokinetic changes of tofacitinib in rat model of diabetes mellitus iduced by streptoztocin
- 주제(키워드) Tofacitinib , CYP3A4 , Diabetes mellitus , Streptozotocin
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2019
- 학위수여년월 2019. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000028519
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib that was approved by FDA is prescribed for the treatment of rheumatoid arthritis (RA). However, tofacitinib was not well known about the pharmacokinetic study of rat model. According to recent report, it has been associated with elevated odds of having arthritis in patients with diabetes. Moreover, the rat model of diabetes mellitus was reported that expression of cytochrome P450 (CYP 450) is changed in hepatic and intestinal. And tofacitinib was known to be metabolized in human primarily via hepatic CYP3A4 followed by CYP2C19, and it is known as substrate of P-glycoprotein. The pharmacokinetics of tofacitinib were compared after intravenous (10 mg/kg) and oral (20 mg/kg) administration, respectively, in a rat group of diabetes mellitus induced by streptozotocin (DMS), and control rats. Hence, the time averaged non-renal clearance (CLNR) value of tofacitinib was expected to be faster than control rats. As expected the CLNR (increased to 143% of control rats) value of tofacitinib was significantly faster in rat group of DMS after intravenous administration. As a result, the total area under the plasma concentration–time curve from time zero to time infinity (AUC0-∞) was significantly smaller in a rat group of DMS (decreased to 33.6% of control rats). Interestingly, volume of distribution of steady state (Vss) value was greater in a rat group of DMS (increased to 361% of control rats). After oral administration, the AUC0-8h in plasma value was also significantly smaller in rat group of DMS (decreased to 55.5% of control rats) and more pronounced than intravenous study. Moreover, disappearance of tofacitinib in hepatic microsomal was indicated that the maximum velocity of disappearance (Vmax) was also significantly increased (increased to 118% of control rats). The intrinsic clearance (CLint) of hepatic was significantly faster than control rats (increased to 212% of control rats). In intestinal microsome, the CLint was not a difference between the rat group of DMS and control rats. In rat group of DMS, the protein expression of CYP3A4 in hepatic was increased than control rats. Moreover, the protein expression of P-gp was increased in intestine.
more목차
Ⅰ. INTRODUCTION 1
Ⅱ. METHOD 5
A. Chemicals 5
B. Animal and maintenance 5
C. Induction of diabetes mellitus rats 5
D. Preliminary study 6
E. Intravenous and oral administration of tofacitinib 6
F. Tissue distribution of tofacitinib in rat 7
G. In vitro metabolism of tofacitinib in the hepatic and intestinal microsomal 7
H. Protein expression of CYP 450 and P-gp 8
I. HPLC analysis of tofacitinib 9
J. Pharmacokinetics analysis 9
K. Statistical analysis 10
Ⅲ. RESULTS 11
A. Preliminary study 11
B. Pharmacokinetics of tofacitinib after intravenous administration 13
C. Pharmacokinetics of tofacitinib after oral administration 16
D. Tissue distribution of tofacitinib concentration in rat after intravenous administration 19
E. In vitro metabolism of tofacitinib in the hepatic and intestinal microsome 21
F. Protein expression of CYP 450 and P-gp 25
Ⅳ. DISCUSSION 27
Ⅴ. CONCLUSION 30
REFERENCES 31
KOREAN ABSTRACT 35
