흰쥐에서 레스베라트롤 및 리코찰콘이 로살탄의 생체이용률에 미치는 영향

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레스베라트롤 또는 리코찰콘과 로살탄의 병용투여가 순환기 질환 예방 및 치료를 위해서 처방되는 경우가 있으므로 이에 대한 상호작용을 알아보기 위해서 흰쥐에 로살탄 (9 mg/kg)과 레스베라트롤 (0.4, 2.0 and 8.0 mg/kg) 또는 리코찰콘 (0.4, 2.0 and 8.0 mg/kg)을 병용 경구투여한 후 로살탄 및 그 활성대사체인 EXP-3174의 약동학적 변수들을 대조군과 비교 검토하였다.
레스베라트롤 또는 리코찰콘과 병용 투여시 로살탄의 약물동태학적 변수는 유의성 있게 변화하였다. 대조군에 비해 레스베라트롤 (2.0 and 8.0 mg/kg) 또는 리코찰콘 (2.0 and 8.0 mg/kg)과 병용투여군에서 로살탄의 혈장농도곡선하면적 (AUC0-◇)과 최고혈중농도 (Cmax)는 각각 유의성있게 증가되었으며, 전신클리어런스는 유의성 있게 각각 감소되었다. 절대적 생체이용률은 대조군에 비해 각각 유의성 있게 증가되었으며 상대적 생체이용률은 1.25-1.63배 증가되었다.
정맥투여군에서는 레스베라트롤 또는 리코찰콘은 로살탄의 약동학적 변수에는 거의 영향을 주지못하였다.
레스베라트롤 (8.0 mg/kg) 또는 리코찰콘 (8.0 mg/kg)과 로살탄을 병용투여한군에서 대조군에 비해 활성대사체인 EXP-3174의 혈장농도곡선하면적 (AUC0-◇)이 증가되었으나 유의성은 없었다. 그리고 레스베라트롤 또는 리코찰콘은 로살탄의 대사율 (M.R.)을 각각 유의성 있게 감소시켰다. 레스베라트롤 및 리코찰콘에 의해서P-gp와 CYP3A 및 CYP2C9활성을 억제시켰으나 리코찰콘이 레스베라트롤 보다 CYP3A4와 P-gp억제효과가 더 컸다.
본 연구에서 항산화작용 및 심혈관 개선작용이 있는 레스베라트롤 또는 리코찰콘을 각각 고혈압치료제인 로살탄과 병용투여 하였을 때 경구투여된 로살탄의 생체이용률이 유의성 있게 증가된 것은 레스베라트롤 및 리코찰콘에 의해서 신배설 감소 보다는 주로 소장에 존재하는 P-gp억제에 의한 흡수증가와, 주로 소장과 간장에 존재하는 CYP3A와 CYP2C9억제에 의한 로살탄의 초회통과효과(대사) 감소와 전신클리어런스의 감소에 기인한 것으로 사료된다.|Resveratrol or licocharcon A and losartan, a calcium channel blocker, could be prescribed as a combination therapy for prevention or treatment of cardiovascular diseases. The purpose of this study was to investigate the possible effects of resveratrol or licocharcon A, on the pharmacokinetics of losartan and its main metabolite, EXP-3174, in rats.
The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral and intravenous administration of losartan (9 or 3 mg/kg) to rats in the presence and absence of resveratrol (0.4, 2 and 8 mg/kg) or licocharcon A (0.4, 2 and 8 mg/kg). The effect of resveratrol or licocharcon A on the P-glycoprotein (P-gp) as well as CYP3A4 and 2C9 activity was also evaluated. Resveratrol or licocharcon A significantly inhibited CYP3A4 and CYP2C9 enzyme. In addition, resveratrol or licocharcon A significantly reduced rhodamine-123 efflux via P-gp in MCF-7/ADR cell overexpressing p-gp. Licocharcon A is more effective than resveratrol in inhibitory effect of P-gp and CYP3A4 activity.
Compared to the control (losartan alone), resveratrol or licocharcon A significantly altered the pharmacokinetic parameters of losartan. The area under the plasma concentration-time curve (AUC0?C◇) and the peak plasma concentration (Cmax) of losartan were significantly increased in the presence of resveratrol or licocharcon A, respectively. The total body clearance (CL/F) was significantly decreased by resveratrol and licocharcon A, respectively. Consequently, the absolute bioavailability of losartan in the presence of resveratrol or licocharcon A were significantly higher than that of the control group, respectively. Pharmacokinetics parameters of intravenous losartan were not affected by resveratrol or licocharcon A.
Resveratrol or licocharcon A increased the AUC0?C◇ of its main metabolite, EXP-3174, respectively, but they are not significxant. Moreover, the metabolite-parent AUC ratio (M.R.) in the presence of resveratrol or licocharcon A were significantly decreased compared to those of the control group, respectively.
In conclusion, the enhanced oral bioavailability of losartan by resveratrol or licocharcon A may result from decreased P-gp-mediated efflux in small intestine and inhibition of CYP 3A- and CYP2C9-mediated metabolism in small intestine and/or in the liver and reduction of total body clearace of losartan.
Based on the results, if the drug interactions are confirmed in the patients with cardiovascular diseases, the dosage of losartan should be readjusted when losartan is used concomitantly with resveratrol or licocharcon A.

Key words: Losartan ∙ EXP-3174 ∙ Resveratrol ∙ Licocharcon A ∙ CYP3A ∙ CYP2C9 ∙ P-gp ∙ Pharmacokinetics ∙ Bioavailability ∙ Rats
Alternative Title
Effects of resveratrol and licocharcon A on the bioavailability of losartan in rats
Alternative Author(s)
Hong-Moog Son
조선대학교 OO대학원
일반대학원 생명약학
Awarded Date
Table Of Contents
Part I. Effects of Resveratrol on the Bioavailability of Losartan in Rats

Materials and Methods∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼10
Animal studies∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼10
Drug administration∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼11
HPLC assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼11
CYP inhibition assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼12
Rhodamine-123 retention assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼13
Pharmacokinetic analysis∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼14
Statistical analysis∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼15
Inhibition of CYP3A4 and CYP2C9∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼16
Rhodamine-123 retention assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼16
Effect of resveratrol on the pharmacokinetics of oral losartan∼∼∼∼∼∼16
Effect of resveratrol on the pharmacokinetics of EXP-3174∼∼∼∼∼∼∼17
Effect of resveratrol on the pharmacokinetics of intravenous losartan∼∼∼17

Part II. Effects of licocharcon A on the Bioavailability of Losartan in Rats

Materials and Methods∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼44
Animal studies∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼44
Drug administration∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼45
HPLC assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼45
CYP3A4 and 2C9 inhibition assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼46
Rhodamine-123 retention assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼47
Pharmacokinetic analysis∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼48
Statistical analysis∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼48
Inhibition of CYP3A4 and 2C9∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼50
Rhodamine-123 retention assay∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼∼50
Effects of licocharcon A on the pharmacokinetics of oral losartan∼∼∼∼∼50
Effects of licocharcon A on the pharmacokinetics of EXP-3174∼∼∼51
Effects of lococharcon A on the pharmacokinetics of intravenous losartan∼52
손홍묵. (2011). 흰쥐에서 레스베라트롤 및 리코찰콘이 로살탄의 생체이용률에 미치는 영향.
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