Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

[Advances in the pharmacological study of Morus alba L].

Morus alba L. (mulberry) is a well-known deciduous tree, belonging to the genus of Morus of Moraceae famlily. Its leaves, twigs, roots (bark) and fruits are widely used in the traditional Chinese medicine. The active constituents of mulberry contained flavonoids, alkaloids, steroids, coumarins, with the significant hypoglycemic, hypolipidemic, antihypertension, anti-oxidation, anti-inflammatory, anti-bacterial, anti-tumor and immunomodulatory activities. This review summarized the research progress of the major pharmacological activity, pharmacokinetics and drug-drug interaction based on CYPs and transporters of mulberry and its active constituents.

Chemical-pharmacokinetic-pharmacodynamic fingerprints of Schisandra chinensis alcoholic extract.

It is valuable to establish a chemical-pharmacokinetic (PK)-pharmacodynamics (PD) fingerprint of traditional Chinese medicine (TCM) for comprehensively understanding the TCM integrated conception and revealing the material foundation. The chemical, metabolic in vitro, and PK/PD in vivo fingerprints of Schisandra chinensis (SC) alcoholic extract were established and comparatively analyzed using HPLC-UV-MS method, rat liver microsomes in vitro and CCl4 intoxicated rats in vivo. Four known effective lignans, schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin, were detected as the standard references in SC alcoholic extract with high concentration. SC alcoholic extract and four lignans when incubated with rat liver microsomes produced several metabolites in NAPDH-dependent manner. Chemical fingerprint of some components with bioactivities were also identified in PK and PD fingerprints in normal and ALI rats that explained the material foundation of SC alcoholic extract for multiple pharmacological effects. Schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin could be considered as the "PK marker" of SC alcoholic extract or its relevant preparations, while two metabolites of the four lignans, 7, 8-dihydroxy-schizandrin and another one (M(W) 432), could be recognized as drug-metabolism (DM) Marker. This work provides experimental data for the further studies of metabolism or material foundation of SC components.

[Effects of Schisandra chinensis (Wuweizi) constituents on the activity of hepatic microsomal CYP450 isozymes in rats detected by using a cocktail probe substrates method].

Effects of constituents from Schisandra chinensis (Wuweizi) on six liver microsomal CYP450 isozymes (CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1 and CYP3A1/2) were studied in rats in vivo and in vitro. The in vitro incubation was conducted using liver microsomes of rats after multiple dosing of alcoholic/water extract from Schisandra chinensis. A HPLC-MS method was applied to determine the metabolites formation of six CYP450s probe substrates (phenacetin-CYP1A2, dextromethorphan-CYP2D2, diclofenac sodium-CYP2C6, mephenytoin-CYP2C11, chlorzoxazone-CYP2E1 and midazolam-CYP3A1/2) in rat liver microsomal incubations. The activity of CYP450 isozymes were represented by the formation of metabolites. Alcoholic extract of Schisandra chinensis (28-120 microg x mL(-1)) showed significant inhibitory effect on six CYP450 isozymes to a certain extent in vitro. Multiple dosing of Schisandra chinensis alcoholic extract (1.5 g x kg(-1), qd x 7d) had significant induction on CYP2E1 and CYP3A1/2, inhibition on CYP2D2 and CYP2C11, and no effect on CYP2C6 and CYP1A2. Water extract of Schisandra chinensis (100-500 microg x mL(-1)) also exhibited inhibition on the activity of CYP450 isozymes in vitro, whereas multiple administrations (1.5 g x kg(-1), qd x 7d) had significant induction of CYP2E1 and inhibition on CYP2D2, no effect on CYP2C6, CYP3A1/2, CYP1A2 or CYP2C11. The results suggested that the constituents from Schisandra chinensis exhibited the inhibition and induction on six rat liver microsomal CYP450 isozymes to a certain extent in vivo and in vitro. The possibility of interaction between Schisandra chinensis and coadministrative drugs will be considered base on the levels and subtype of CYP450 involved in the drug metabolism.

Simultaneous quantification of four active schisandra lignans from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using liquid chromatography/mass spectrometry.

A simple, rapid and sensitive method was developed for the simultaneous quantification of four active schisandra lignans (schisandrin, schisantherin A, deoxyshisandrin and gamma-schisandrin) from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using a high-performance liquid chromatography system coupled to a positive ion electrospray mass spectrometric analysis. The plasma sample preparation was a simple deproteinization by the addition of three volumes of methanol followed by centrifugation. The analytes and internal standard (IS) bicyclol were separated on a Zorbax SB-C18 column (3.5 microm, 2.1 mm x 100 mm) with mobile phase of methanol/water (70:30, v/v) containing 0.1% formic acid at a flow rate of 0.2 mL/min with an operating temperature of 25 degrees C. Detection was performed on a Trap XCT mass spectrometer equipped with an electrospray ionization (ESI) source operated in selected ion monitoring (SIM) mode. Positive ion ESI was used to form sodium adduct molecular ions at m/z 455 for schisandrin, m/z 559 for schisantherin A, m/z 439 for deoxyshisandrin, m/z 423 for gamma-schisandrin, and m/z 413 for the internal standard bicyclol. Linear detection responses were obtained for the four test compounds ranging from 0.010 to 2.0 microg/mL and the lower limits of quantitation (LLOQs) for four lignans were 0.010 microg/mL. The intra- and inter-day precisions (R.S.D.%) were within 12.5% for all analytes, while the deviation of assay accuracies was within +/-13.0%. The average recoveries of analytes were greater than 80.0%. All analytes were proved to be stable during all sample storage, preparation and analytic procedures. The method was successfully applied to the pharmacokinetic study of the four lignans after oral administration of Schisandra chinensis extraction to rats.