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Streptozotocin으로 유도된 당뇨 모델에서의 tofacitinib의 약동학적 변화
- Alternative Title
- Eunhye GWAK
- Author(s)
- 곽은혜
- Alternative Author(s)
- Eunhye GWAK
- Advisor
- 김소희
- Department
- 일반대학원 약학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2019-02
- Language
- eng
- Alternative Abstract
- 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.
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- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 3. Theses(Master)
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