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Er-Zhi-Wan (EZW) is a traditional Chinese medicine with many clinical applications and used as a health product in East Asia. Five active ingredients (salidroside, specnuezhenide, nuezhenoside, luteolin, and oleanolic acid) were screened out from EZW to develop an in vitro rapid evaluation method for the classification of in vivo drug absorption behavior by biopharmaceutics classification system (BCS). Ultra-performance liquid chromatography was used for quantitative analysis. Solubility and permeability were assayed by equilibrium solubility and multiple models: everted rat intestinal sac model, cultured Caco-2 cells, octanol-water partition coefficient (LogP) method. The BCS properties of drugs were predicted using software applications, and the correlations of measured and predicted values of factors affecting oral drug absorption were calculated. The results were verified by measuring the absolute bioavailability of the active ingredients. Salidroside, specnuezhenide, and nuezhenoside were classified as BCS class III drugs, and luteolin was classified as a BCS class III/I drug because of the difference in LogP and intestinal permeability. Oleanolic acid was classified as a BCS class II/IV drug in acidic media and BCS class I/III drug in other media. Overall, EZW may be classified as a BCS class III drug, and permeability was identified as the primary factor limiting absorption. The results provide a novel method for the evaluation of the in vivo absorption of oral traditional Chinese medicines., (© 2019 John Wiley & Sons, Ltd.)

A rapid, sensitive and specific ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of shanzhiside methyl ester, 8-O-acetylshanzhiside methyl ester and luteolin-7-O-β-D-glucopyranoside of Lamiophlomis rotata Pill in rat plasma was developed and validated. After liquid-liquid extraction with n-butyl alcohol/ethyl acetate (70:30, v/v), analytes and paeoniflorin (internal standard, IS) were separated on an Acquity BEH UPLC C18 column (100 × 2.1 mm, 1.7 μm) with gradient elution at a flow rate of 0.2 mL/min. All calibration curves had good linearity (r>0.9929) over the concentration ranges of 1-1000 ng/mL for shanzhiside methyl ester and 8-O-acetylshanzhiside methyl ester, 0.3-150 ng/mL for luteolin-7-O-β-D-glucopyranoside. The intra- and inter-day precisions were all within 11.1% and the accuracy (relative error, RE%) all ranged from -13.6% to 5.3%. The method also guaranteed an acceptable selectivity, recovery and stability, which was successfully applied to a pharmacokinetic study of the three analytes in rats after oral administration of Lamiophlomis rotata Pill., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A rapid, sensitive and selective ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method for the simultaneous determination of three active flavonoid glycosides: luteolin-7-O-gentiobioside, luteolin-7-O-β-D-glucoside and luteolin-7-O-β-D-glucuronide in beagle dog plasma was developed and validated. Puerarin was used as internal standard (IS). After protein precipitation with acidified acetonitrile, the analytes were separated on a Venusil MP C18 column with a gradient elution system composed of 0.05% formic acid and acetonitrile at a flow rate of 0.4ml/min. Detection was performed using multiple reaction monitoring (MRM) mode with a turbo ion spray source under a negative ionization condition. The calibration curves of the three analytes showed good linearity (r>0.995) within the tested concentration ranges. The lower limits of quantification for luteolin-7-O-gentiobioside, luteolin-7-O-β-D-glucoside and luteolin-7-O-β-D-glucuronide were 1.0 ng/ml, 1.0 ng/ml and 4.0 ng/ml, respectively. The intra-day and inter-day precision and accuracy deviations were less than 15%, and the extraction recoveries of the three analytes from beagle dog plasma were more than 75%. The validated method was successfully applied to a pharmacokinetic study of the three flavonoid glycosides in beagle dog plasma after intravenous administration of the traditional Chinese medicinal preparation: Kudiezi injection., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To establish a UPLC-MS/MS analysical method for simultaneous determination of concentrations of isoorientin, scutellarin and cynaroside in rat plasma and to study their pharmacokinetic characteristics after intravenous injection of 3 doses of Fufang Hongcao in rats., Method: Acidified plasma samples were precipitated for protein with methanol. Waters Acquity BEH C18 column was adopted for spectrum, with mobile phase as 0. 1% formic acid acetonitrile-0. 1% formic acid-water gradient elution. Detection was carried out by the multiple reaction monitoring (MRM) positive ion mode with ESI ionization source., Result: Three flavonoids show a good linear relationship, with the extraction recovery ranging between 78.56% and 101.91% and a high intra-and inter-day precisions and accuracy. The MRT of the three flavonoids were all lower than 22 min in rats., Conclusion: The above men tioned method is so specific, rapid, sensitive that it is suitable for pharmacokinetic studies of Fufang Hongcao injection in rats.

Luteolin (3',4',5,7-tetrahydroxyflavone) and apigenin (4',5,7-trihydroxyflavone) are two common flavones and major bioactive components in Flos Chrysanthemi extract (FCE). Although FCE contains approximately equal amounts of luteolin (6.5%, w/w) and apigenin (5.4%, w/w), luteolin showed a much lower exposure than apigenin when FCE was orally administered to rats. The aim of the present study is to elucidate the mechanisms that caused the pharmacokinetic difference between luteolin and apigenin in rats. The results of an in situ rat intestinal single-pass perfusion model showed that the permeability of luteolin (k(a), 7.96×10⁻² min⁻¹ and P(eff), 4.87×10⁻³ cm/min) was about 50% that of apigenin (k(a), 18.5×10⁻² min⁻¹ and P(eff), 10.8×10⁻³ cm/min), which agreed with the observation that oral bioavailability of luteolin (30.4%) from FCE was significantly lower than that of apigenin (51.1%). On the other hand, luteolin was much more unstable than apigenin during the incubation with primary rat hepatocytes, and methylated metabolites of luteolin were detected after incubation. In addition, further metabolism of methylated luteolin also contributed to the faster elimination of luteolin. In conclusion, luteolin and apigenin are very similar in structure, however, one-hydroxyl difference gives them different characteristics in absorption and metabolism, which results in much lower exposure of luteolin than apigenin when FCE is orally administered to rats.

The study is aimed to establish a RP-HPLC method for determination of luteolin from the extracts of Elsholtzia blanda (EEB) in rats' biological specimen. A RP-HPLC method was established for determination of free and total luteolin in SD rats' plasma and gastrointestinal tract and total luteolin in SD rats' heart, liver, lung and kidney at 0.17, 0.5, 1, 2, 4 and 6 h after administration of EEB to 24 male SD rats (4 rats per one time spot). Luteolin glycoside was hydrolyzed to aglycone luteolin in intestinal tract, and then luteolin was absorbed. The main form of luteolin existed in gastrointestinal tract after administration of EEB is aglycone. The content of luteolin in liver and kidney were higher than that in heart and lung. The content of luteolin in kidney, heart and lung were showed max at 1 h. Its peak time was similar to that in blood. However, in liver, the drug was distributed quickly, and showed max at 0.17 h. And because of the sensitivity of the method, luteolin was not be detected in other tissues. The method is sensitive, specific, accurate, and is appropriate for determination of luteolin in vivo.