랫드의 고지혈 상태가 JAK 1/3 억제제인 tofacitinib의 pharmacokinetics에 미치는 영향
Effect of hyperlipidemic status on the pharmacokinetics of tofacitinib, a JAK 1/3 inhibitor, in rats
- 주제(키워드) tofacitinib , hyperlipidemia , poloxamer 407 , CYP3A4 , high-cholesterol diet , pharmacokinetics , triglyceride
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2020
- 학위수여년월 2020. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000029704
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib은 Janus kinase 1,3 경로를 표적으로 차단하여 염증을 감소시키는 류마티스 관절염 치료제이며, Cytochrome P450 (CYP) 3A4와 2C19에 의해 대사 된다. 본 연구에서는 쥐에게 poloxamer 407-Hyperlipidemia (PHL)과 1% 콜레스테롤과 0.5% 콜산-Hyperlipidemia (DHL)을 함유한 식이로 고지혈을 유발하여 정맥(10 mg/kg) 및 경구 투여(20 mg/kg)에서의 약동학적 변화를 살펴 보았다. 조직 고정에서 PHL은 대조군에 비해 간에서 차이가 없었으나 DHL은 대조군에 비해 107% 더 높았으며, 심한 지방 변화는 대조군에서 관찰되지 않았으며 염증과 괴사도 일부에서 관찰되었다. PHL 쥐에서 AUC0-∞ (the total area under the plasma concentration-time curve from time zero to infinity)는 대조군에 비해 느린 CLNR (the time averaged non-renal clearance)에 의해 약 57.7% 증가하였다. 반면에 DHL 쥐에서 AUC0-∞는 대조군에 비해 빠른 CLNR에 의해 약 29.9% 감소하였다. 간 microsome의 enzyme activity에서 PHL 쥐는 Vmax (maximum velocity of disappearance)가 약 62.1% 감소하여 CLint (intrinsic clearance)가 17.3% 감소하였다. 반면에 DHL 쥐는 Vmax 가 약 77.3% 증가하여 CLint가 약 61.9% 증가하였다. Immunoblot analysis결과에서는 PHL 쥐에서 CYP3A의 발현이 감소하였으나, DHL 쥐에서 발현이 유도됨을 알 수 있었다. 종합해보면, tofacitinib의 약동학적 변화는 고지혈증 상태에 의존적이며, 중성지방은 CYP 효소의 발현에 중요한 역할을 할 것이다. 또한, triglyceride와 CYP 효소 발현에 대한 추가적인 연구가 필요하다.
more초록/요약
Tofacitinib, a Janus kinase 1 and 3 inhibitor, was developed for treatment of rheumatoid arthritis. Recently, hyperlipidemia is increasing in patients with rheumatoid arthritis. In this study, poloxamer 407-induced hyperlipidemic (PHL) and diet containing 1% cholesterol and 0.5% cholic acid-induced hyperlipidemic (DHL) rat models were employed. These two models have high LDL-cholesterol levels but the difference is high triglyceride level in PHL model but low in DHL model. The pharmacokinetic changes of tofacitinib after intravenous (10 mg/kg) and oral administration (20 mg/kg) of the drug were evaluated in poloxamer 407-induced hyperlipidemic (PHL) and diet containing 1% cholesterol and 0.5% cholic acid-induced hyperlipidemic (DHL) rat models. In PHL rats, area under the plasma concentration-time curve from time zero to time infinity (AUC) of toracitinib was significantly increased by 57.7% due to slower time-averaged non-renal clearance (CLNR) compared to their control rats. In DHL rat, AUC of tofacitinib was significantly decreased by 29.9% due to faster CLNR compared to their control rats. In vitro metabolism study confirmed that intrinsic clearance (CLint) were significantly decreased by 17.3% in PHL hepatic microsome and significantly increased by 61.9% in DHL hepatic microsome, respectively. Protein expression of cytochrome P450 (CYP) 3A1(23) was decreased in PHL model but induced in DHL model, respectively. Taken together, the pharmacokinetic changes of tofacitinib were dependent on the hyperlipidemic status and triglyceride might play a role for the expression of CYP enzymes. Further investigation between triglyceride levels and CYP enzyme expression were needed
more목차
Ⅰ. INTRODUCTION 1
Ⅱ.METERIALS AND METHODS 4
A. Materials 4
B. Animals 4
C. Induction of hyperlipidemia 5
D. Preliminary study 7
E. Pharmacokinetics of tofacitinib in PHL and DHL rat model 8
F. Tissue distribution 9
G. In vitro metabolism 9
H. Immunoblot analysis 10
I. HPLC analysis of tofacitinib 11
J. Pharmacokinetic analysis 12
K. Statistical analysis 12
Ⅲ. RESULTS 13
A. Effect of body weight, food intake and food efficiency in diet-induced hyperlipidemic rat model 13
B. Preliminary Study 15
C. Pharmacokinetics of tofacitinib after intravenous and oral administration in PHL rat model 19
D. Pharmacokinetics of tofacitinib after intravenous and oral administration in DHL rat model 23
E. Tissue distribution of tofacitinib in PHL and DHL rat models 27
F. Measurement of Km, Vmax and CLint of tofacitinib in hepatic microsome 31
G. Protein expression of CYP isozymes 33
Ⅳ. DISCUSSION 35
Ⅴ. CONCLUSION 39
REFERENCES 40
KOREAN ABSTRACT 45
