Effects of posaconazole on the metabolism of tofacitinib in rats
- 주제(키워드) tofacitinib , posaconazole , pharmacokinetics , drug interaction , non-competitive inhibition , [I] / Ki , CYP3A4
- 주제(DDC) 615.1
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2022
- 학위수여년월 2022. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000031816
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Fungal infections frequently occur in patients with autoimmune diseases who are getting immunosuppressive therapy. Tofacitinib, used for the treatment of rheumatoid arthritis, is an inhibitor of Janus kinase that affects immune cell function, and is metabolized by Cytochrome P450 (CYP) 3A4 and 2C19. Posaconazole, a triazole antifungal agent, is not metabolized by the CYP enzyme, but inhibits CYP3A4. In this study, based on the characteristics of these two drugs, the pharmacokinetic drug interactions were investigated by intravenous and oral administration of tofacitinib and posaconazole alone or in combination to rats. As a result, the total area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of tofacitinib for intravenous and oral co-administration increased by 167 % and 77.0 %, respectively, and the time-averaged non-renal clearance (CLNR) of tofacitinib decreased by 64.6 % than that after intravenous administration of tofacitinib alone. In vitro metabolism of tofacitinib using rat hepatic and intestinal microsomes showed that posaconazole inhibited the metabolism of tofacitinib at a non-competitive manner. The concentration in the liver and intestine ([I]) / apparent inhibitory constant (Ki) ratios of posaconazole showed greater than 1, suggesting that tofacitinib has a high drug interaction potential with posaconazole. Immunoblot analysis also showed that posaconazole inhibited the expression of CYP3A4. However, tofacitinib had no significant effects on the pharmacokinetics of posaconazole. In conclusion, posaconazole inhibits the metabolism of tofacitinib by non-competitively inhibiting CYP3A4, which resulted in a significant increase in AUC0-∞ and a decrease in CLNR of tofacitinib when co-administered with posaconazole to rats.
more초록/요약
진균 감염은 면역 억제 치료를 받는 자가 면역 질환자들에게서 빈번히 발생한다. 토파시티닙은 면역 세포 기능에 관여하는 Janus kinase 의 억제제로 주로 류마티스 관절염 치료에 쓰이며, Cytochrome P450 (CYP) 3A4 와 2C19 에 의해 대사된다. 포사코나졸은 트리아졸계 항진균제이며, CYP 효소에 의해 대사되진 않지만 CYP3A4 를 억제한다. 그래서 본 연구에서는 이러한 두 약물의 각 특성들에 기반하여 토파시티닙과 포사코나졸을 rat 의 정맥 및 경구의 각 투여 경로로 단독 그리고 병용 투여하여 약동학적 약물과 약물 간의 상호작용을 알아보고자 하였다. 결과적으로 rat 의 정맥-, 경구- 병용 투여에서 토파시티닙의 The total area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) 는 정맥-, 경구- 단독 투여에서 보다 각각 167 %, 77.0 % 증가하였으며, 정맥- 병용 투여에서 토파시티닙의 Time-averaged non-renal clearance (CLNR) 은 정맥- 단독 투여에서 보다 64.6 % 감소하였다. In vitro 에서 rat 의 간과 장 microsomes 을 통한 약물 대사 실험에서 포사코나졸은 비경쟁적으로 토파시티닙의 대사를 억제했다. 1 보다 큰 값을 나타낸 rat 의 간과 장에서의 포사코나졸의 농도 ([I]) / 포사코나졸의 겉보기 억제 상수 (Ki) 비로부터 포사코나졸은 높은 가능성으로 CYP 효소에 의한 토파시티닙의 대사를 억제했다. Immunoblot 분석 실험을 통한 CYP 효소의 발현 정도로 포사코나졸은 CYP3A4 을 억제했다. 토파시티닙은 포사코나졸의 약동학에 유의한 영향을 미치지 않았다. 결론적으로 포사코나졸은 토파시티닙의 대사에 관여하는 CYP 효소 중 CYP3A4 을 비경쟁적으로 저해하며, 이는 rat 에서 유의한 토파시티닙의 AUC0-∞ 증가와 CLNR 감소의 결과를 가져왔다.
more목차
Ⅰ. INTRODUCTION 1
Ⅱ. MATERIALS AND METHODS 5
A. Chemicals 5
B. Animals 6
C. Single and co- administration of tofacitinib, posaconazole intravenously and orally in rats 6
D. Metabolism of tofacitinib through rat hepatic and intestinal microsomes in vitro in the absence and presence of posaconazole 8
E. Determination of enzyme activity against tofacitinib by rat hepatic and intestinal microsomes 10
F. Estimation of binding of tofacitinib to proteins in rat plasma 11
G. Measurement of posaconazole concentrations in the liver and intestine after intravenous and oral administration of tofacitinib and posaconazole in rats 12
H. Immunoblot analysis of rat hepatic and intestinal microsomes 13
I. HPLC analysis 14
J. Pharmacokinetic analysis 15
K. Statistical analysis 16
Ⅲ. RESULTS 17
A. Pharmacokinetics of tofacitinib after intravenous and oral administration of tofacitinib and posaconazole in rats 17
B. Pharmacokinetics of posaconazole after intravenous and oral administration of posaconazole and tofacitinib in rats 20
C. Vmax, Km, and CLint of tofacitinib and Ki of posaconazole from non-competitive inhibition of tofacitinib metabolism by posaconazole in rat hepatic and intestinal microsomes 24
D. Binding of tofacitinib to proteins in rat plasma in the absence and presence of posaconazole 30
E. Concentrations of posaconazole and [I] / Ki ratios of posaconazole in the liver and intestine after intravenous and oral administration of tofacitinib and posaconazole in rats 30
F. Protein expression levels of CYP2C11 and CYP3A1/2 35
Ⅳ. DISCUSSION 37
Ⅴ. CONCLUSION 41
REFERENCES 43
KOREAN ABSTRACT 46
