Abstract
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.
Highlights
Berberine (BBR, structure was shown in Fig.1A), an isoquinoline alkaloid, is an important bioactive component isolated from the rhizome of Coptis chinensis (‘‘Huang-Lian’’ in Chinese) of Ranunculaceae family
Optimization and Validation In this study, LC/MSn-IT-TOF combined with triple quadrupole high performance liquid chromatography–mass spectrometry (HPLC-MS)/MS was first used for the qualitative and quantitative analysis of BBR and its metabolites in the investigation of tissue distribution
The lower limit of quantification (LLOQ) of the assay was at 0.05 ng/ ml
Summary
Berberine (BBR, structure was shown in Fig.1A), an isoquinoline alkaloid, is an important bioactive component isolated from the rhizome of Coptis chinensis (‘‘Huang-Lian’’ in Chinese) of Ranunculaceae family. BBR has been used as antimicrobial for a long history in China. Besides its anti-microbial effect [1,2,3,4], BBR has been used in clinic for hyperlipidemia [5], diabetes [6], neuroprotective [7] and cardiovascular diseases [8], suggesting its potential in future. BBR showed anti-hyperlipidemia effect of lowering total cholesterol (TC), triglyceride (TG), low-densitylipoprotein cholesterol (LDL-c) levels in patients [5]. The cholesterol-lowering mechanism of BBR was different from that of statins. Statins up-regulate the low density lipoprotein receptor (LDLR) via inhibiting cholesterol synthesis, while BBR elevates the LDLR expression by stabilizing LDLR message ribonucleic acid (mRNA). BBR itself is the most active form, its metabolites remain active with 30–70% activity [9]. For LDLR up-regulation and adenosine 59-monophosphateactivated protein kinase (AMPK) activation, berberrubine and thalifendine are the two active metabolites, but with reduced potency [9]
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