Tofacitinib의 대사 유도제 및 억제제에 따른 약물 동태학
Effects of cytochrome P450 (CYP) inducers and inhibitors on tofacitinib pharmacokinetics in rats
- 주제(키워드) tofacitinib , pharmacokinetic , induction , inhibition
- 발행기관 아주대학교
- 지도교수 김소희, 김수동
- 발행년도 2018
- 학위수여년월 2018. 2
- 학위명 석사
- 학과 및 전공 글로벌제약임상대학원 글로벌제약임상약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000027640
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Hepatic microsomal cytochrome P450 (CYP) isozymes are important for the in vitro and in vivo metabolism of tofacitinib in rats. However, the study that which types of CYP isozymes are related have not been reported yet. In this study, in vitro to confirm that tofacitinib is metabolized by specific CYP. Furthermore, we conducted inhibitor kinetics experiments with specific inhibitors (ketoconazole, fluconazole, fluvoxamine). Vmax is the same, and Km value is different, it can be confirmed that it is a competitive inhibitor. In order to prove the in vitro we further proceeded with the in vivo experiment. Tofacitinib at a dose of 10 mg/kg was intravenously administered to rats pretreated with various inducers of CYP isozymes, such as dexamethasone, rifampicin, omeprazole and orphenadrine (the main inducers of CYP3A4, 2C9/19, 1A1/2, 2B1/2) and inhibitors, such as SKF 525A (a non-specific of inhibitor of CYP isozymes), ketoconazole, fluconazole, fluvoxamine and quinidine (the main inhibitors of CYP3A4, 2C19, 2C9 and 2D6). In rats pretreated with dexamethasone phosphate and rifampicin, the time-averaged nonrenal clearance (CLNR) was outstandingly faster (232 and 49.2% increase) than those in control rats. In rats pretreated with ketoconazole and fluconazole, the CLNR was outstandingly slower (45.4 and 38.7% decrease) than those in control rats. Taken together, the results suggest that tofacitinib is predominantly metabolized via the CYP3A4 and 2C19 in rats.
more목차
I. INTRODUCTION 1
II. METHOD 3
A. Chemicals 3
B. Animals 3
C. In vitrometabolism by rat liver microsomes 4
D. Pretreatment with CYP inducers and inhibitorsin rats 6
E. Intravenous study 7
F. HPLC analysis of tofacitinib 8
G. Pharmacokinetics analysis 9
H. Statistical analysis 10
III. RESULTS 11
A. Tofacitinib metabolism in liver microsomes 11
B. Measurement of Vmaxand Kmfor disappearance of tofacitinib pretreated with various CYP inhibitors in liver microsomes 14
C. Tofacitinib metabolism in liver microsomes pretreated with various CYP inducers 18
D. Pharmacokinetics of tofacitinib after its intravenous administration to rats pretreated with various CYP inducers 20
E. Pharmacokinetics of tofacitinib after its intravenous administration to rats pretreated with various CYP inhibitors 25
IV. DISCUSSION 29
V. CONCLUSION 31
REFERENCES 32
KOREAN ABSTRACT 35
