| Objective: Wen Shen Kechuan Tablet, which is a new Chinese prescription of effectiveparts, is composed of the extracts of Radix Glycyrrhiza by waters and ethanol, and theextracts of Cortex Magnoliae Officinalis and Fructus Cnidii by CO2supercriticaltechnology. The prescription has the effective of warming the kidney to improve inspiration,relieving cough and asthma. Glycyrrhizic acid, honokiol, magnolol, osthole and imperatorinare the principal active constituent of Wen Shen Kechuan Tablet. Cytochrome P450enzymeis the most important drug-metabolizing enzyme in liver, and the quality of induction andinhibition is the cause of drug-drug interaction in clinical, than ti would been reflected inthe pharmacokinetics.There are studises that Cortex Magnoliae Officinalis has littlenephrotoxicity, and the nephrotoxicity is related to the content of magnolol, but themethanism is not clear. Radix Glycyrrhiza has a wide range of pharmacological activity,such as harmonize the property of drug and detoxity. So more research should be put for theeffect of major constituent of Wen Shen Kechuan Tablet on the cytochrome P450expression and its pharmacokinetic, and explore the potential biomarker of the CortexMagnoliae Officinalis nephrotoxicity and the prescription deintoxication, it can provide adependable basis for development of the clinical application of this prescription.Methods: By using HepG2cells in vitro system and fluorescent dye SYBY GREEN, in thisstudy we quantitate mRNA expression in the HepG2cell by real-time quantitative PCR.;At different intervals (0,1,2,4,6,10,24,30,36,48,50,60) after administration ofglycyrrhizic acid, honokiol, magnolol, osthole and imperatotin mixture(3:4:4:3:3), and thesingle constituent. And the concentration of glycyrrhetinic acid, magnolol, osthole,imperatorin was detected in the rat plasma, and comparing the pharmanokinetics ofdifferent constituent in single and both by PK packages of R software;Select the SD animal, dividing three group: control group and Cortex Magnolia Officinalis group and Wen ShenKechuan Tablet prescription group, determine the function indexes of GOT, AST, AST, ALP,CRE, BUN after dosing13days, and analysis the rat urine by ulterperformance liquidchromatography-mass spectrometry and analysis the data by MixOmics and stability-basedbiomarker selection packages of R software.Result: Glycyrrhizi acid and liquiritigenin would induce the expression of CYP1A2,liquiritin and the mixture of Glycyrrhiza active constituent would inhibit the expression ofCYP1A2, CYP2E1and CYP3A4enzyme.,the mixture of Glycyrrhiza active constituentcould induce the expression of CYP2D6, however magnolol and imperation couldsignificantly increase the expression of CYP1A2,2E1and3A4, honokiol and ostholewould increase the expression of CYP2E1and CYP3A4. The pharmacokinetics paramatersof the constituent in the compound and single constituent were compared. Hydrocxylatedhonokiol conjulated with glucuromic sulfurin acid and honokiol monoglucuromide werefound in rat plsmas after oral administration of honokiol. The constituent of glycyrrheneticacid, magnolol, osthole, imperatorin, Hydrocxylated honokiol conjulated with glucuromicsulfurin acid and honokiol monoglucuromide had higher Cmax and AUC0lim in theprescription than in the single constituent. Both male and female rat would have kidneytoxicity by adminidtered with Cortex Magnolia Officinalis, and find the biomarkerphoshorycholine, kynurenine,2,8-dihydroxy adenine, docosenoic acid and phoshory-choline,2-methylestrone, tetrahydro corticosterone,814.5464,407.0359,461.1833,respetively. Howerver, we didn’t find kidney toxicity when combining Cortex MagnoliaOfficinalis with Glycyrrhiza uralensis, Fructus Cnidii on female animals and male animals,and find the detoxification biomarker is related to Sulfosalicylic acid and homocysteinefor male animals. And the biomarker defferent between Cortex Magnolia Officinalis andadmixture are phoshorycholine, docosenoic acid, Sulfosalicylic acid, homocysteine,xanthurenic acid,2-oxoglutaric acid, p-Cresol sulfat,3-hydroxytetradecanedionic acid onmale animals, but did not find any biomarker for female animalsConclusion: The level of CYP expression could be significantly induced or inhibited bythose different constituent, and the result supply the evidence for the interaction of herb-drug based on cytochrome P450and toxicity, so care shoud be taken when WenshenKechuan Tablet are co-administered with other drugs.The constituents in the prescriptionhad delayed absorption, a longer residence time, a higher Cmax and AUC, than those in thesingle constituent. Thernfore, they were more efficient and durable, The metabonomicsresults of Cortex Magnolia Officinalis show that it related to the pharmamacological. Thetocitvity of Cortex Magnolia Officinalis could significantly reduce after combineing withGlycyrrhiza Uralensis and Ftuctus Cnidii. To some extent, it can reveal the compatibility ofWenshenkechuan Tablet. |
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