Liquid chromatography–tandem mass spectrometry analysis of protocatechuic aldehyde and its phase I and II metabolites in rat

Xu, Mei; Zhang, Zichuan; Fu, Gang; Sun, Shi-feng; Sun, Jianghao; Yang, Min; Liu, Aihua; Han, Jian; Guo, De‐An

doi:10.1016/j.jchromb.2007.05.042

Cited by 46 publications

(41 citation statements)

References 32 publications

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“…The major metabolite of 22 was M22 2M , which was poorly eliminated via renal excretion. Protocatechuic aldehyde has been reported to convert into protocatechuic acid by ALDH (Panoutsopoulos and Beedham, 2005;Xu et al, 2007). Consistent with this, the total Cum.A e-U,0-24h of protocatechuic acid (2) and its metabolites (including M2 M , M2 M-G-1 , M2 M-G-2 , M2 S-1 , and M2 S-2 ) after dosing exceeded the amount of 2 dosed from DanHong injection by 28-fold.…”

Section: Resultssupporting

confidence: 66%

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

Wang

Huang

et al. 2015

Drug Metab Dispos

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DanHong injection is a Danshen (Salvia miltiorrhiza roots)-based injectable solution for treatment of coronary artery disease and ischemic stroke. Danshen catechols are believed to be responsible for the injection's therapeutic effects. This study aimed to characterize systemic exposure to and elimination of Danshen catechols in human subjects, rats, and dogs receiving intravenous DanHong injection. A total of 28 catechols were detected, with content levels of 0.002-7.066 mM in the injection, and the major compounds included tanshinol, protocatechuic aldehyde, salvianolic acid B, rosmarinic acid, salvianolic acids A and D, and lithospermic acid with their daily doses ‡10 mmol/subject. After dosing, tanshinol, salvianolic acid D, and lithospermic acid exhibited considerable exposure in human subjects and rats. However, only tanshinol had considerable exposure in dogs. The considerable exposure to tanshinol was due to its having the highest dose, whereas that to salvianolic acid D and lithospermic acid was due to their relatively long elimination half-lives in the human subjects and rats. Protocatechuic aldehyde and rosmarinic acid circulated in the bloodstream predominantly as metabolites; salvianolic acids A and B exhibited low plasma levels with their human plasma metabolites little or not detected. Tanshinol and salvianolic acid D were eliminated mainly via renal excretion. Elimination of other catechols involved hepatobiliary and/or renal excretion of their metabolites. Methylation was found to be the primary metabolism for most Danshen catechols and showed intercompound and interspecies differences in rate and degree in vitro. The information gained here is relevant to pharmacological and toxicological research on DanHong injection.

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Section: Resultssupporting

confidence: 66%

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

Wang

Huang

et al. 2015

Drug Metab Dispos

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“…We found that PCA was subject to extensive presystemic hepatic elimination and degradation in the erythrocytes. Purified PCA can be biotransformed in vivo into protocatechuic acid (Xu et al, 2007a); aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase may mediate the metabolism (Panoutsopoulos and Beedham 2005). In the current study, we found the concentration of protocatechuic acid in plasma and urine was in the low nanogram per milliliter range after administration of cardiotonic pills.…”

Section: Discussionmentioning

confidence: 99%

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 Metab Dispos

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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“…2. Furthermore, after being processed with MDF, their possible metabolites were detected in combination with related literature data or METLIN's metabolite mass spectral database [23][24][25][26][27][28][29] and showed in Table 3. Fig.…”

Section: Identification Of the Metabolites Of G Longituba Extract Inmentioning

confidence: 99%

UPLC–QTOF/MS-based screening and identification of the constituents and their metabolites in rat plasma and urine after oral administration of Glechoma longituba extract

Qian

Duan

et al. 2010

Journal of Chromatography B

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Liquid chromatography–tandem mass spectrometry analysis of protocatechuic aldehyde and its phase I and II metabolites in rat

Cited by 46 publications

References 32 publications

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

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

UPLC–QTOF/MS-based screening and identification of the constituents and their metabolites in rat plasma and urine after oral administration of Glechoma longituba extract

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