Pharmacokinetic drug interaction between voriconazole and tofacitinib in rat
- 주제(키워드) tofacitinib , voriconazole , pharmacokinetics , noncompetitive inhibition , CYP3A4 , CYP2C19
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2021
- 학위수여년월 2021. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000030591
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tofacitinib has been demonstrated to treat rheumatoid arthritis (RA) as a Janus kinase (JAK) inhibitor (Fleischmann et al, 2012), among which it is a small molecule inhibitor specifically targeted for inhibition of JAK 1 and JAK 3 (Meyer et al, 2010). Citinib is also effective as a treatment for ulcerative colitis (Agnès et al, 2018). JAK is a downstream signaling molecule in many cytokine pathways involved in inflammatory bowel disease (IBD). When cytokines bind to cell surface receptors, ligand receptors dimerize, causing phosphorylation of JAK molecules. JAK then activates the signal transducer and activate of transcription molecules (STAT), which phosphorylation moves pass STAT to the nucleus and activate gene transcription (Soendergaard et al, 2018). By targeting the JAK signal, it can affect several cytokine pathways thought to be associated with colitis. The pharmacokinetics of tofacitinib are metabolized in the liver at about 70% clearance and excreted by the kidneys at about 30% clearance of the total clearance. In the liver clearance mechanism, CYP3A4 is mainly about 50% and CYP2C19 about 20% less (Dowty et al, 2014). Voriconazole is a triazole-based antifungal agent used in the treatment of candidiasis and aspergillus. According to the recent US guidelines, voriconazole has been recommended as a first-line therapy for aspergillosis (Misch and Safdar 2016).The mechanism of action of voriconazole is the inhibition of the cytochrome P450 (CYP450) dependent 14α lanosterol demethylation, an consequential echelon in the synthesis of cell membrane ergosterol, similar to other triazoles (Sanati et al, 1997). The metabolism of voriconazole show up in the liver through a family of CYP450 enzymes, including CYP2C9, CYP3A4, and CYP2C19 homologous enzymes. Metabolites have no antifungal activity. The activity of the CYP2C19 pathway, the main metabolic pathway of voriconazole, is highly dependant on genetic properties (Louis et al, 2003). The potential for drug interaction with voriconazole is high due to metabolism by the CYP 450 isoenzyme (Hoffman et al, 2002) The pharmacokinetics of voriconazole is most metabolized in the liver and is driven by CYP3A4. The half-life is approximately 6 hours and protein binding is about 58% (Changcheng et al, 2019). Tofacitinib is administered with antifungal agents such as voriconazole due to the risk of fungal infections such as upper respiratory tract infections (Yong et al, 2017). The purpose of this study is tofacitinib and voriconazole alone and in combination. It is to measure the blood concentration and pharmacokinetic parameters of drugs that change through co-administration. As a result, it is expected to be data for pharmacokinetic studies of tofacitinib and triazole-based drugs.
more목차
1.INTRODUCTION 1
2.METERIALS AND METHODS 4
2.1 Materials 4
2.2 Animals 4
2.3 In vivo studies 5
2.4 In vitro studies 6
2.5 HPLC analysis of tofacitinib and voriconazole 9
2.6 Pharmacokinetic analysis 11
2.7 Statistical analysis 11
3. RESULTS 12
3.1 The drug plasma concentration and pharmacokinetic parameters of tofacitinib, which are determined after the single intravenous administration of tofacitinib to rat and the co-administration of tofacitinib and voriconazole 12
3.2 The drug plasma concentration and pharmacokinetic parameters of tofacitinib, which are determined after the single oral administration of tofacitinib to rat and the co-administration of tofacitinib and voriconazole 14
3.3 The drug plasma concentration and pharmacokinetic parameters of voriconazole, which are determined after the single intravenous administration of voriconazole to rat and the co-administration of voriconazole and tofacitinib 17
3.4 The drug plasma concentration and pharmacokinetic parameters of voriconazole, which are determined after the single oral administration of voriconazole to rat and the co-administration of voriconazole and tofacitinib 18
3.5 Measure the concentration of drugs in the liver after intravenous and oral administration of tofacitinib and voriconazole to rats 21
3.6 Measurement of Vmax, km and CLint according to voriconazole concentration 23
3.7 Non-competitive inhibition of tofacitinib metabolism by voriconazole in rat liver microsomes 25
3.8 Protein expression of CYP isozymes 27
4. DISCUSSION 29
5. CONCLUSION 31
6. REFERENCES 32
