Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat
Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat
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DOI：
10.1055/s-2004-815490
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发表时间：
2004-02-01
期刊：
影响因子：
2.7
通讯作者：
Li, JX
中科院分区：
文献类型：
--
作者：
Zhang, Y;Akao, T;Li, JX
我们评估了丹参的主要多酚成分和具有多种药理活性的有效抗氧化剂丹酚酸镁B（MLB）的生物利用度，以评价其在体内的作用。在以4和20 mg/kg剂量静脉给予MLB至Fats后，紫草酸B（LSB）的血浆浓度显示双指数下降。浓度-时间曲线下面积值（AUC; 87.8 +/- 10.9和1130 +/- 329 μ g.min/mL），总清除率（CLtot; 55.52 +/- 7.07和23.51 +/- 5.98 mL/min/kg）和稳态分布容积（V-ss; 7.60 +/- 1.03和3.61 +/- 1.16 L/ kg）表明两种剂量之间的非线性药代动力学。在以100 mg/kg的高剂量经口给予MLB后，平均AUC仅为1.26 +/- 0.36 μ g.min/mL。根据20 mg/kg静脉给药和100 mg/kg经口给药后的AUC值，计算MLB的绝对生物利用度为0.0002。极低的生物利用度主要是由于大鼠胃肠道吸收不良所致;在原位空肠袢实验中，即使在经口给药后4小时，约65%的剂量仍保留在肠道中，即使在输注后20分钟，大部分剂量仍保留在肠道中。尽管CL和V值较大，但在静脉注射后30 h内，LSB的尿液和胆汁排泄分别仅为0.70% +/- 0.26%和5.10% +/-2.36%，经口给药后更低（+/- 0.010% 0.001%和0.12% +/- 0.04%）。这些结果表明，广泛的代谢，包括首过效应，以及广泛的LSB分布，除了吸收不良，导致全身生物利用度极低。
We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to Fats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 mug.min/mL), total body clearance (CLtot; 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V-ss; 7.60 +/- 1.03 and 3.61 +/- 1.16 L/ kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 mug.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65% of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70% +/- 0.26% and 5.10% +/- 2.36%, respectively, over a 30 h time period after intravenous injection despite the large CL, and V, values, and were much less (+/- 0.010% 0.001 % and 0.12% +/- 0.04%) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.