Metabolism and disposition of resveratrol in rats: Extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model
Metabolism and disposition of resveratrol in rats: Extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model
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DOI：
10.1124/jpet.102.033340
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发表时间：
2002-07-01
影响因子：
3.5
通讯作者：
Ducharme, MP
中科院分区：
文献类型：
--
作者：
Marier, JF;Vachon, P;Ducharme, MP
研究了其糖苷配基（RESAGL）和葡糖苷酸（RESGLU）形式的反式白藜芦醇在静脉内（15 mg/kg i. v.）和经口（50 mg/kg p.o.）将在β-环糊精溶液中的反式-白藜芦醇施用至完整大鼠。此外，在大鼠模型中评估了RESAGL和RESGLU的肝肠再循环。采集多份血浆和尿液样本，并使用电喷雾电离-液相色谱/串联质谱法测定RESAGL和RESGLU的浓度。静脉给药后，RESAGL的血浆浓度下降，消除半衰期迅速（T-1/2，0.13 h），随后在给药后4 - 8 h血浆浓度突然升高。这些血浆浓度导致RESAGL的终末消除半衰期显著延长（T-1/2 TER，1.31 h）。RESAGL和RESGLU在口服给药后4至8 h也显示血浆浓度突然增加，T-1/2 TER分别为1.48和1.58 h。RESAGL的生物利用度为38%，其暴露量约为RESGLU的46倍（AUC（inf），7.1 vs. 324.7 mumol.h/l）。在连接大鼠模型中证实了肝肠再循环，因为在4 - 8 h时在胆汁受体大鼠中观察到显著的RESAGL和RESGLU血浆浓度。RESAGL和RESGLU的暴露百分比分别为24.7%和24.0%，这是由于肠肝再循环。12小时内尿液中排泄的药物分数可忽略不计。这些结果证实了RESAGL具有生物利用度，并经历了广泛的首过葡萄糖醛酸化，并且肝肠再循环显著促进了大鼠中RESAGL和RESGLU的暴露。
Pharmacokinetics of trans-resveratrol in its aglycone (RESAGL) and glucuronide (RESGLU) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of beta-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RESAGL and RESGLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RESAGL and RESGLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RESAGL declined with a rapid elimination half-life (T-1/2, 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RESAGL (T-1/2TER, 1.31 h). RESAGL and RESGLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T-1/2TER of 1.48 and 1.58 h, respectively. RESAGL bioavailability was 38% and its exposure was approximately 46-fold lower than that of RESGLU (AUC(inf), 7.1 versus 324.7 mumol.h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RESAGL and RESGLU were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RESAGL and RESGLU that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RESAGL is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RESAGL and RESGLU in rats.