흰쥐에서 항산화제인 실리비닌이 로살탄의
- Issued Date
- 2010
- Abstract
- Abstract
The present study was to investigate the effect of silibinin, an antioxidant, on the bioavailability and pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. The pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral administration of losartan (9 mg/kg) in the presence or absence of silibinin (0.3, 1.5 and 6 mg/kg). The effect of silibinin on the P-glycoprotein (P-gp), CYP 3A4 and CYP2C9 activity was also evaluated. Silibinin inhibited CYP3A4 and CYP2C9 enzyme activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 1.97 and 5.25 μM, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of losartan were significantly altered by silibinin compared with those in the control group. The presence of silibinin significantly (p < 0.05, 1.5 mg/kg; p < 0.01, 6 mg/kg) increased the area under the plasma concentration–time curve (AUC0–∞) of losartan by 40.8–68.4% and the peak plasma concentration (Cmax) of losartan by 40.6–69.3%. Consequently, the absolute bioavailability (A.B.) of losartan in the presence of silibinin was 35.8–42.8%, which was enhanced significantly (p < 0.05) compared with that in the oral control group (25.4%). The relative bioavailability (R.B.) of losartan was increased by 1.41- to 1.68-fold over that in the control group. However, there were no significant changes in the time to reach the peak plasma concentration (Tmax) and the terminal half-life (t1/2) of losartan in the presence of silibinin. Silibinin (6 mg/kg) significantly increased the AUC (28.6%) of EXP-3174 compared with that in the control group. The metabolite-parent AUC ratio (M.R.) was significantly (p < 0.05) decreased by 32.1–35.8 % in the presence of silibinin (1.5 and 6 mg/kg) compared to that in the control group, implying that coadministration of silibinin could inhibit the CYP3A and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver and the P-gp efflux pump in the small intestine. In conclusion, silibinin significantly enhanced the oral bioavailability of losartan, suggesting that concurrent use of silibinin and losartan should be monitored closely for potential drug interactions.
Key words: losartan, EXP-3174, silibinin, bioavailability, pharmacokinetics, P-gp, CYP3A4, CYP2C9, rat
- Alternative Title
- Effects of silibinin, an antioxidant, on the bioavailability of Losartan in Rats
- Alternative Author(s)
- Jae-seong Lee
- Department
- 일반대학원 식품의약학과
- Advisor
- 최준식
- Awarded Date
- 2010-08
- Table Of Contents
- Abstract ……………………………………………………1
국문초록……………………………………………………4
1. Introduction………………………………………………5
2. Materials and Methods…………………………………7
2.1. Materials…………………………………………………7
2.2. Animal studies…………………………………………7
2.3. Drug administration……………………………………7
2.4. Mathod and assay………………………………………8
2.4.1. HPLC assay……………………………………………8
2.4.2. CYP inhibition assay…………………………………9
2.4.3. Rhodamine-123 retention assay……………………10
2.5. Pharmacokinetic analysis……………………………10
2.6. Statistical analysis……………………………………11
3. Results……………………………………………………12
3.1. Inhibition of CYP3A4 and CYP2C9…………………12
3.2. Rhodamine-123 retention assay……………………12
3.3. Effect of silibinin on the pharmacokinetics of losartan 12
3.4. Effect of silibinin on the pharmacokinetics of active metabolite,EXP-3174………………12
4. Discussion…………………………………………………14
5. Conclusion………………………………………………16
References…………………………………………………17
LIST OF TABLES
Table 1. Mean pharmacokinetic parameters of losartan after intravenous (3 mg/kg) or oral (9 mg/kg) administration of losartan to rats in the presence or absence of silibinin (mean ± SD, n = 6) …………………28
Table 2. Mean pharmacokinetic parameters of EXP-3174 after oral administration of losartan (9 mg/kg) to rats in the presence and absence of silibinin (mean ± SD, n = 6)…29
LIST OF FIGURES
Figure 1. The HPLC chromatograms of the rat’s blank plasma (A) and the plasma spiked with L-158.809 (internal standard; 6.3 min), losartan (11.4 min) and EXP-3174 (17.8 min). …….………………………23
Figure 2. Inhibitory effect of silibinin on CYP3A4 (A) and 2C9 (B) activity. All experiments were performed in duplicate, and results are expressed as the percent of inhibition..…………………………………………………24
Figure 3. Effect of silibinin on the cellular accumulation of rhodamine-123 in MCF-7 and MCF-7/ADR cells. Data represents mean SD of 6 separate samples (significant versus control MCF-7 cells, ** p < 0.01). ………25
Figure 4. Mean plasma concentration-time profiles of losartan after intravenous (3 mg/kg) and oral (9 mg/kg) administration of losartan to rats in the presence or absence of silibinin (0.3, 1.5 and 6 mg/kg) (mean ± SD, n = 6, each). Bars represent the standard deviation: (●) Oral administration of losartan (9 mg/kg; control); (○) with 0.3 mg/kg of silibinin; (▼) with 1.5 mg/kg of silibinin; (▽) with 6 mg/kg of silibinin; (■) Intravenous administration of losartan (3 mg/kg). …………………………………26
Figure 5. Mean plasma concentration-time profiles of EXP-3174 after oral (9 mg/kg) administration of losartan to rats in the presence or absence of silibinin (0.3, 1.5 and 6 mg/kg) (mean ± SD, n = 6, each). Bars represent the standard deviation: (●) Oral administration of losartan (9 mg/kg); (○) with 0.3 mg/kg of silibinin; (▼) with 1.5 mg/kg of silibinin; (△) with 6 mg/kg of silibinin.………27
- Degree
- Master
- Publisher
- 조선대학교 대학원
- Citation
- 이재성. (2010). 흰쥐에서 항산화제인 실리비닌이 로살탄의.
- Type
- Dissertation
- URI
- https://oak.chosun.ac.kr/handle/2020.oak/8840
http://chosun.dcollection.net/common/orgView/200000240342
- Appears in Collections:
- General Graduate School > 3. Theses(Master)
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