Structural characterization of metabolites of salvianolic acid B from Salvia miltiorrhiza in normal and antibiotic-treated rats by liquid chromatography–mass spectrometry

Xu, Mei; Guo, Hui; Han, Jian; Sun, Shi-feng; Liu, Aihua; Wang, Baorong; Ma, Xiaochi; Liu, Peng; Qiao, Xue; Zhang, Zichuan; Guo, Dan

doi:10.1016/j.jchromb.2007.08.032

Cited by 40 publications

(27 citation statements)

References 44 publications

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“…Many methylated and underlying methylated conjugates of SAA abundant in drug-containing bile provide convincing evidence for the predominance of its in vivo methylation pathway in rat. These findings also reveal that in rats, SAA is prone to undergoing rapid hepatic metabolism and high biliary excretion in the form of methylated conjugates, which is similar to the metabolic characteristics observed in some other natural phenolic acids, including salvianolic acid B (SAB), caffeic acid, and rosmarinic acid (Baba et al, 2004;Xu et al, 2007;Lv et al, 2010).…”

Section: Resultssupporting

confidence: 67%

Metabolism of Salvianolic Acid A and Antioxidant Activities of Its Methylated Metabolites

Che

et al. 2014

Drug Metabolism and Disposition

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This study investigated the metabolism of salvianolic acid A (SAA) both in vivo and in vitro. Liquid chromatography-mass spectrometry analysis of drug-containing rat bile samples and bile samples hydrolyzed by glucuronidase revealed a series of methylated conjugates of SAA and its glucuronides, as well as the predominance of the methylation pathway of SAA in rats. For the first time, four major methylated metabolites present in vivo were prepared for structure characterization and bioactivity evaluation using in vitro coincubation systems with rat hepatic cytosol protein as the enzyme donor. By using nuclear magnetic resonance imaging and other spectroscopic methods, these metabolites were unambiguously elucidated as 3-O-methyl-SAA (M1), 39-O-methyl-SAA (M2), 3,30-O-dimethyl-SAA (M3), and 39,30-O-dimethyl-SAA (M4), respectively. Along with results from the enzyme inhibition study, selective formation of these meta-O-methylated derivatives indicated that catechol O-methyltransferase (COMT) is responsible for methylated transformation of SAA. All of these metabolites displayed fairly high antioxidant potency against in vitro rat liver lipid peroxidation with halfmaximal inhibitory concentrations that were much lower than those of the positive controls and even SAA. Overall, the results from this study demonstrate that SAA is a metabolically unstable compound that undergoes rapid methylation metabolism catalyzed by COMT, and these generated O-methylated metabolites may be largely responsible for its in vivo pharmacological effects.

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Section: Resultssupporting

confidence: 67%

Metabolism of Salvianolic Acid A and Antioxidant Activities of Its Methylated Metabolites

Che

et al. 2014

Drug Metabolism and Disposition

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“…receiving SAA, SAB, SAD, RMA, and LSA on separate occasions, which is in agreement with the observation with p.o. SAB in rats by Xu et al (2007b).…”

Section: Discussionmentioning

confidence: 98%

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Tong¹,

Yang²,

Gao³

et al. 2008

Drug Metabolism and Disposition

117

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ABSTRACT:Cardiotonic pills are a type of cardiovascular herbal medicine. To identify suitable pharmacokinetic (PK) marker(s) for indicating systemic exposure to cardiotonic pills, we examined the in vivo PK properties of putatively active phenolic acids from the component herb Danshen (Radix Salviae miltiorrhizae). We also performed in vitro and in silico assessments of permeability and solubility. Several phenolic acids were investigated, including tanshinol (TSL); protocatechuic aldehyde (PCA); salvianolic acids A, B, and D; rosmarinic acid; and lithospermic acid. Plasma TSL exhibited the appropriate PK properties in dogs, including dose-dependent systemic exposure in area under concentration-time curve (AUC) and a 0.5-h elimination half-life. In rats, more than 60% of i.v. TSL was excreted intact into the urine. In humans, we found a significant correlation between the urinary recovery of TSL and its plasma AUC. The absorption rate and bioavailability of TSL were not significantly different whether cardiotonic pills were given p.o. or sublingually. The gender specificity in plasma AUC disappeared after body-weight normalization, but the renal excretion of TSL was significantly greater in women than in men. PCA was predicted to be highly permeable according to in vitro and in silico studies; however, extensive presystemic hepatic elimination and degradation in the erythrocytes led to extremely low plasma levels and poor dose proportionality. Integrated in vivo, in vitro, and in silico studies on the other phenolic acids showed poor gut permeability and nearly undetectable levels in plasma and urine. In conclusion, plasma and urinary TSL are promising PK markers for cardiotonic pills at the tested dose levels.The use of herbal therapies is escalating worldwide. However, the basis for the therapeutic effects is often poorly interpreted, and the safety, dose, and potential herb-drug interactions require better estimation (Fugh-Berman, 2000;De Smet, 2002;Lazar, 2004). Unlike most synthetic drugs, herbal medicinal products usually contain numerous chemical constituents, especially traditional Chinese medicines that often use a combination of multiple herbs.Determining which constituents of an herbal product have favorable drug-like properties will extend our knowledge of the basis for pharmacological efficacy and safety. An herbal constituent can be defined as drug-like when it possesses the desired potency, a wide safety margin, and appropriate pharmacokinetic (PK) properties and exists in adequate abundance in the herbal product. A deficit in these properties limits the usefulness of the herbal constituent for the herbal product. For a drug, the pharmacologic effect is attained when the drug or its active metabolite reaches and sustains an adequate concentration at an appropriate site of action; this hypothesis should also be applied to the herbal product. Both the dose levels and fates of active constituents in the body govern their target-site concentrations after administration of an herbal product. The releva...

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“…However, the metabolism of these compounds has not been well clarified. Although LC-MS had been widely used for the metabolism studies and structure analysis as a sensitive and reliable approach [8][9][10], most of the research had focused on the metabolism of certain constituents after dosing of Danshen crude drug or compound Danshen recipe. We have earlier reported the metabolic study on the total phenolic acids of Danshen in rat urine and feces, and detected and identified five metabolites [11].…”

Section: Introductionmentioning

confidence: 99%

Metabolic analysis of four phenolic acids in rat by liquid chromatography–tandem mass spectrometry

Zhang

Sun

et al. 2008

Journal of Chromatography B

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Structural characterization of metabolites of salvianolic acid B from Salvia miltiorrhiza in normal and antibiotic-treated rats by liquid chromatography–mass spectrometry

Cited by 40 publications

References 44 publications

Metabolism of Salvianolic Acid A and Antioxidant Activities of Its Methylated Metabolites

Metabolism of Salvianolic Acid A and Antioxidant Activities of Its Methylated Metabolites

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Metabolic analysis of four phenolic acids in rat by liquid chromatography–tandem mass spectrometry

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