Tissue distribution of berberine and its metabolites after oral administration in rats.
Tissue distribution of berberine and its metabolites after oral administration in rats.
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DOI：
10.1371/journal.pone.0077969
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jiang JD
中科院分区：
文献类型：
--
作者：
Tan XS;Ma JY;Feng R;Ma C;Chen WJ;Sun YP;Fu J;Huang M;He CY;Shou JW;He WY;Wang Y;Jiang JD
小檗碱（BBR）具有降胆固醇、抗糖尿病、心血管保护和抗炎等多种生物活性，在临床上已被证实。然而，BBR的血浆水平非常低，无法解释其在患者中的药理作用。我们认为BBR及其生物活性代谢产物的体内分布可能为这个问题提供了部分解释。在本研究中，采用液相色谱-离子阱飞行时间质谱（LC/MSn-IT-TOF）以及液相色谱-串联质谱（LC-MS/MS）研究大鼠经口给药（200 mg/kg）后BBR的组织分布和药代动力学。结果表明，BBR在肝脏、肾脏、肌肉、肺、脑、心脏、胰腺和脂肪中分布迅速，分布量由大到小依次为：肝脏>肾脏>肌肉>肺>脑>心脏>胰腺>脂肪。药代动力学曲线表明，给药后4 h，大多数组织中BBR的水平高于（或远高于）血浆中的水平。BBR在肝脏、心脏、脑、肌肉、胰腺等组织中相对稳定，其代谢产物的器官分布也与BBR的器官分布相一致。在肝、肾等器官中检测到的代谢产物中，沙利芬定（M1）、小檗红碱（M2）和药根碱（M4）具有中等的生物活性。例如，M1、M2和M4是肝脏中的主要代谢物，其中M2的百分比高达65.1%; BBR或代谢物在肝脏中的AUC（0-t）（浓度-时间曲线下面积）水平分别是血浆中的10倍和30倍。总之，经口给药后，BBR（及其生物活性代谢产物）的器官浓度高于其血液浓度。这可能解释了BBR在临床上对人类疾病的药理作用。
Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR’s plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MSn-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR’s level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR’s metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR’s pharmacological effects on human diseases in clinic.
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