Baicalein 6-<i>O</i>-β-d-Glucopyranuronoside Is a Main Metabolite in the Plasma after Oral Administration of Baicalin, a Flavone Glucuronide of Scutellariae Radix, to Rats

Abstract

Baicalin (BG) and its aglycone, baicalein (B) are strong antioxidants that exert various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to identify major metabolite(s) besides BG in rat plasma after oral administration of BG or B. The main metabolite was detected by HPLC equipped with an electrochemical detector at a potential of +500 mV and identified as baicalein 6-O-β-d-glucopyranuronoside (B6G) by HPLC/MS/MS. When BG at a dose of 20 mg/kg was administered orally to Wistar rats, the level of B6G in plasma was higher than that of BG. C max and the area under the concentration-curve from 0 to 24 h (AUC 0-24 h ) values of the plasma B6G were 1.66±0.34 µm and 19.8±3.9 µm·h, respectively, whereas those of BG were 0.853±0.065 µm and 10.0±3.1 µm·h, respectively. When B was administered, similar results were also obtained. B6G-producing activities from B were found in microsomes of both rat jejunum and liver, in spite of the low activity. Rat everted jejunal sacs formed B6G after application of B, but only in a small amount that was excreted into the mucosal side, and not the serosal side, indicating little contribution to the appearance of B6G in plasma. On the other hand, when B was injected into the rat portal vein, B6G was detected at a higher level than BG in the systemic circulation, demonstrating the hepatic contribution to the appearance of plasma B6G.Key words baicalin; baicalein 6-O-β-d-glucopyranuronoside; metabolite; rat Scutellariae Radix, the root of Scutellaria baicalensis GeorGi (Labiatae), is used in combination with other herbs in Chinese traditional (Kampo, in Japanese) medicines, and contains baicalin (BG, 5,6,7-trihydroxyflavone-7-β-d-glucuronide; Fig. 1) as its main active constituent. BG and its aglycone, baicalein (B), have wide-ranging pharmacological effects, such as antiallergic, 1) anti-inflammatory, 2) antiviral, 3,4) antiproliferative, 5) and antitumor 6) effects, and also show strong antioxidant activity. 7,8) In addition, they inhibit prostaglandin E2 production, and prevent the gene expression of inducible nitric oxide synthase and cyclooxygenase-2. 9) B also has an anxiolytic-like effect 10) and a protective effect against amnesia. 11)BG has been detected in rat plasma after its oral administration, 12) suggesting that it is absorbed directly from the gastrointestinal tract. However, in our previous study when BG was given to germ-free rats, only a small amount of BG was detected in their plasma. In addition, BG, and not B, has been detected even after oral administration of B to rats. 13) On the other hand, many kinds of metabolites such as B-glucuronides and B-sulfates besides BG have been found in bile after oral administration of either BG or B to rats.14) Many kinds of B-metabolites have also been detected in bile and urine after oral administration of Scutellariae Radix extract or Chinese traditional medicines that include Scutellariae Radix. 15) In addition, unidentified metabolites besides BG in rat plasma have been found ...

Flavonoids are identified from the extract of Scutellariae Radix to suppress inflammatory-induced angiogenic responses in cultured RAW 264.7 macrophages

“…After oral administration of SR for 5 days in rat model, the level of PGE2 in LPS-stimulated macrophages was reduced robustly, and the pharmacodynamic interaction was proposed to be via the Cox–2 pathway 40 . The major metabolites were reported to be baicalin and baicalein by utilizing HPLC coupled with electrochemical detector 41 . From the results, AUC 0–24 hour values were 1.66 ± 0.34 µM and 19.8 ± 3.9 µM for baicalin, and 0.853 ± 0.065 µM and 10.0 ± 3.1 µM for baicalein, respectively 41 .…”

“…The major metabolites were reported to be baicalin and baicalein by utilizing HPLC coupled with electrochemical detector 41 . From the results, AUC 0–24 hour values were 1.66 ± 0.34 µM and 19.8 ± 3.9 µM for baicalin, and 0.853 ± 0.065 µM and 10.0 ± 3.1 µM for baicalein, respectively 41 . Furthermore, the pharmacokinetic parameters of baicalin and baicalein, after oral administration of SR, were calculated and analyzed by the pharmacokinetic program 42 .…”

Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice

“…Modulation of nuclear localization of NRF2 in oxidative injury by administration of baicalin analog baicalein has been reported earlier in HepG2 cells and cisplatin nephrotoxicity [ 42 , 43 ]. After administration of baicalein, it modified mainly to its glucuronide analog baicalin in the blood stream with significantly stability (half-life of 11.8 hours) [ 44 , 45 ]. One of the important findings is that the absence of NRF2 can exacerbate NF- κ B activity leading to increased cytokine production, whereas NF- κ B can modulate NRF2 transcription and activity.…”

Treatment with baicalein attenuates methionine−choline deficient diet-induced non-alcoholic steatohepatitis in rats

“…It should be noted that when given by oral administration, glucuronidation of absorbed baicalein in liver could form large amount of baicalin (Akao et al, 2000(Akao et al, , 2013, which is also a strong antioxidant that exerts various pharmacological actions in rats. Furthermore, it was reported that oral administration of baicalein has hapatoprotective effects against CCl 4 -induced liver injury in mice and rats (Huang et al, 2012;Sun et al, 2010).…”