汉黄芩素吸收及代谢机制的研究
|
摘要
汉黄芩素（wogonin），5,7-二羟基-8-甲氧基黄酮（C16H12O5）为唇形科植物黄芩Scutellaria baicalensis Georgi的干燥根中的一种主要活性成分，现代药理研究表明：汉黄芩素具有抗氧化、抗菌、抗炎、抗病毒、抗肿瘤、神经保护等多种作用，目前越来越受到人们的广泛关注。本文通过对其生物药剂学与药物动力学的系统研究，以明确其吸收机制及提高其生物利用度的方法，阐明发生药物相互作用的潜力，拟为该药的剂型设计和临床用药提供理论指导。1.汉黄芩素肠吸收机理的研究
通过Caco-2细胞和大鼠在体单向肠灌流这两种吸收模型对汉黄芩素的肠吸收特征及吸收动力学进行了研究，两种方法都显示汉黄芩素的肠吸收主要以被动扩散方式吸收，其膜转运过程受pH、温度和4%BSA的影响（P<0.01）；药物的分泌不受P-gp抑制剂维拉帕米（VRP）、胞饮抑制剂金刚烷胺、能量代谢抑制剂2，4-二硝基苯酚（DNP）和多药耐药抑制剂MK571的影响（P>0.05），与大鼠在体胃、肠吸收同为被动过程；汉黄芩素在大鼠胃及各肠段均有吸收，但消化道上段的吸收优于下段，符合制成速释、胃漂浮制剂的基本条件。2.汉黄芩素在Beagle犬体内的生物利用度研究
利用溶剂法制备汉黄芩素固体分散体（汉黄芩素:PVP K30=1:5），通过体外溶出度、差示热分析、X-射线衍射等方法确定汉黄芩素在固体分散体中以无定形方式存在；LC-MS/MS内标法测定汉黄芩素固体分散体给药后Beagle犬体内的血药浓度，汉黄芩素在犬体内吸收快，消除慢，其绝对生物利用度约为4.0%，但与原料药相比，生物利用度提高了约679.9%；利用LC/MSn/DAD技术对给药后的Beagle犬血浆进行分析，认为汉黄芩素的葡萄糖醛酸结合物为其主要代谢产物；与固体分散体比较，汉黄芩素盐溶液的相对生物利用度为81.3%；以β-葡萄糖醛酸酶酶解后总的汉黄芩素计算，其Cmax约为血浆中游离汉黄芩素的12倍以上，AUC(0-∞)则超过30倍，MRT(0-t)显著延长（8.38±3.14）v.s.（3.39±1.25）h。3.汉黄芩素对大鼠肝P450同工酶和mdr1的影响
汉黄芩素盐溶液大鼠连续灌胃给药7d（10、30、90mg/kg，qd），各剂量组P450酶含量均有下降趋势，与正常组比较，大剂量组（90mg/kg）显示有统计学差异（P<0.05）。而CYP1A1的表达水平明显下降（低剂量P<0.05，中、高剂量P<0.01），CYP2E1、CYP3A1及mdr1mRNA表达水平则未见明显影响。
本文通过研究汉黄芩素在Caco-2细胞和大鼠在体单向肠灌流这两种吸收模型中的吸收特征，并考察其固体分散体、精氨酸盐溶液在Beagle犬体内的生物利用度，发现在研究剂量范围内，汉黄芩素在两种模型中均具有较好的吸收参数，但口服后绝对生物利用度却很低，故认为，汉黄芩素口服给药绝对生物利用度低的主要原因与其溶解度低及体内较强的II相代谢有关。固体分散体、精氨酸盐溶液相对于原料药能显著提高汉黄芩素的相对生物利用度，Beagle犬给药后体内的主要代谢产物为汉黄芩素与葡萄糖醛酸的结合物；大鼠灌胃给药对P450酶含量有一定的影响并可使CYP1A1的表达水平明显下降，提示汉黄芩素长期用药应注意肝功能的变化，并应避免与CYP1A1的抑制剂同时应用。
Wogonin,5,7-dihydroxy-8-methoxyflavone, is one of the major bioactive flavonoidaglycones isolated from the root of Scutellaria baicalensis Georgi (Fam. Labiatae). In recentyears, wogonin has attracted substantial interest as it possesses antioxidant, antibiosis,anti-inflammatory, anti-hepatitis B virus, cancer-preventive and anticonvulsant effects. Themain objectives of this research were to investigate and clarify the biopharmaceutics andpharmacokinetics characteristics of wogonin, in order to guide design of dosage forms andclinical medication.
1. Investigation on the intestinal absorption mechanism of wogonin
Caco-2cell and single pass intestine perfusion (SPIP) model were used toinvestigate the intestinal absorption kinetics of wogonin. Wogonin was absorbedthrough the epithelia mostly by paracellular pathway. Temperature, pH and BSAaffected its member transport significantly (P<0.01). Inhibitor of P-gp, pinocytosis, cellmetabolism and multi-drug resistance had not influence on wogonin efflux frombasolateral side to apical side (P>0.05). Wogonin can be absorbed by stomach and different position of rat intestine, and the extent of absorption of upper gastrointestinalis superior to that of below gastrointestinal, which provide a theoretical basis for quickrelease forms or intragastric floating drug delivery system of wogonin.
2. Investigation on the bioavailability of wogonin in Beagle dogs
Wogonin solid dispersions were prepared by the solvent method, and characterizeby methods including dissolution, differential scanning calorimetry and power X-raydiffractometry. The bioavailability assessment in Beagle dogs were assayed byLC-MS/MS. It was indicated that wogonin existed in the solid dispersions at amorphousform and that it possibly interacted with PVP K30via hydrogen bond when the ratio ofdrug to the carrier was1:5. Wogonin plasma concentration versus time curve in Beagledogs showed that the solid dispersion approach was associated with a significantdecrease in tmaxand an evident increase in Cmaxcompared to raw substance wogonin.The absolute bioavailability of wogonin solid dispersion was4%, and comparing to rawsubatance wogonin, the relative bioavalability of wogonin in the solid dispersions was679.9%. The major metabolite wogonin-7β-D-glucuronide (W-7-G) in Beagle dogplasma was confirmed by LC/MSn/DAD technology. Comparing to wogonin soliddispersions, the relative bioavalability of arginine-wogonin solution was81.3%. Theconcentration of W-7-G in dog expressed as wogonin equivalent was twelve times tothat of free wogonin in dog plasma, AUC(0-∞)was amplified to thirty times and MRT(0-t)was extended to2.5times.
3. Effects of wogonin administrated by oral on liver microsomal cytochrome P450isoenzyme and mdr1in rats
To evaluate the induction/inhibition action of wogonin on P450isoenzyme andmdr1in rats, the P450content and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b in rat liver after oral administration of wogonin wasanalysed. Male SD rats (n=36) were randomly divided into six groups and givendifferent compounds. P450content in liver microsomes was mearsured by Dual-Beam Spectrophotometric method and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b were assayed with RT-PCR. Oral administration ofwogonin at high dose(90mg/kg) can cause significant declined in the content of P450inrat liver, and at low dose(>10mg/kg) can cause decrease significantly in the mRNAlevel expression of CYP1A1.
In the present study, the absorption of features in Caco-2cell and SPIP model ofwogonin and the bioavalability of wogonin solid dispersions and arginine-wogonin inBeagle dogs were investigated, which showed that the oral bioavability of wogonin waslow although it had good absorption characters. The reasons were that it suffered poordissolution and strong second-phase metabolism to produce conjugated metabolitewogonin-7-beta-glucuronide under the action of UDP-glucuronytransferase. It deservesto investigate some bioactive on the conjugated substance. Oral administration ofwogonin at high dose can cause significant difference in the content of P450in rat liver,and all given doses can cause decrease significantly in the mRNA level expression ofCYP1A1, which suggested that liver function should be pay attention during long termtreatment with wogonin and avoid combine with the inhibitor of CYP1A1in clinical.
通过Caco-2细胞和大鼠在体单向肠灌流这两种吸收模型对汉黄芩素的肠吸收特征及吸收动力学进行了研究，两种方法都显示汉黄芩素的肠吸收主要以被动扩散方式吸收，其膜转运过程受pH、温度和4%BSA的影响（P<0.01）；药物的分泌不受P-gp抑制剂维拉帕米（VRP）、胞饮抑制剂金刚烷胺、能量代谢抑制剂2，4-二硝基苯酚（DNP）和多药耐药抑制剂MK571的影响（P>0.05），与大鼠在体胃、肠吸收同为被动过程；汉黄芩素在大鼠胃及各肠段均有吸收，但消化道上段的吸收优于下段，符合制成速释、胃漂浮制剂的基本条件。2.汉黄芩素在Beagle犬体内的生物利用度研究
利用溶剂法制备汉黄芩素固体分散体（汉黄芩素:PVP K30=1:5），通过体外溶出度、差示热分析、X-射线衍射等方法确定汉黄芩素在固体分散体中以无定形方式存在；LC-MS/MS内标法测定汉黄芩素固体分散体给药后Beagle犬体内的血药浓度，汉黄芩素在犬体内吸收快，消除慢，其绝对生物利用度约为4.0%，但与原料药相比，生物利用度提高了约679.9%；利用LC/MSn/DAD技术对给药后的Beagle犬血浆进行分析，认为汉黄芩素的葡萄糖醛酸结合物为其主要代谢产物；与固体分散体比较，汉黄芩素盐溶液的相对生物利用度为81.3%；以β-葡萄糖醛酸酶酶解后总的汉黄芩素计算，其Cmax约为血浆中游离汉黄芩素的12倍以上，AUC(0-∞)则超过30倍，MRT(0-t)显著延长（8.38±3.14）v.s.（3.39±1.25）h。3.汉黄芩素对大鼠肝P450同工酶和mdr1的影响
汉黄芩素盐溶液大鼠连续灌胃给药7d（10、30、90mg/kg，qd），各剂量组P450酶含量均有下降趋势，与正常组比较，大剂量组（90mg/kg）显示有统计学差异（P<0.05）。而CYP1A1的表达水平明显下降（低剂量P<0.05，中、高剂量P<0.01），CYP2E1、CYP3A1及mdr1mRNA表达水平则未见明显影响。
本文通过研究汉黄芩素在Caco-2细胞和大鼠在体单向肠灌流这两种吸收模型中的吸收特征，并考察其固体分散体、精氨酸盐溶液在Beagle犬体内的生物利用度，发现在研究剂量范围内，汉黄芩素在两种模型中均具有较好的吸收参数，但口服后绝对生物利用度却很低，故认为，汉黄芩素口服给药绝对生物利用度低的主要原因与其溶解度低及体内较强的II相代谢有关。固体分散体、精氨酸盐溶液相对于原料药能显著提高汉黄芩素的相对生物利用度，Beagle犬给药后体内的主要代谢产物为汉黄芩素与葡萄糖醛酸的结合物；大鼠灌胃给药对P450酶含量有一定的影响并可使CYP1A1的表达水平明显下降，提示汉黄芩素长期用药应注意肝功能的变化，并应避免与CYP1A1的抑制剂同时应用。
Wogonin,5,7-dihydroxy-8-methoxyflavone, is one of the major bioactive flavonoidaglycones isolated from the root of Scutellaria baicalensis Georgi (Fam. Labiatae). In recentyears, wogonin has attracted substantial interest as it possesses antioxidant, antibiosis,anti-inflammatory, anti-hepatitis B virus, cancer-preventive and anticonvulsant effects. Themain objectives of this research were to investigate and clarify the biopharmaceutics andpharmacokinetics characteristics of wogonin, in order to guide design of dosage forms andclinical medication.
1. Investigation on the intestinal absorption mechanism of wogonin
Caco-2cell and single pass intestine perfusion (SPIP) model were used toinvestigate the intestinal absorption kinetics of wogonin. Wogonin was absorbedthrough the epithelia mostly by paracellular pathway. Temperature, pH and BSAaffected its member transport significantly (P<0.01). Inhibitor of P-gp, pinocytosis, cellmetabolism and multi-drug resistance had not influence on wogonin efflux frombasolateral side to apical side (P>0.05). Wogonin can be absorbed by stomach and different position of rat intestine, and the extent of absorption of upper gastrointestinalis superior to that of below gastrointestinal, which provide a theoretical basis for quickrelease forms or intragastric floating drug delivery system of wogonin.
2. Investigation on the bioavailability of wogonin in Beagle dogs
Wogonin solid dispersions were prepared by the solvent method, and characterizeby methods including dissolution, differential scanning calorimetry and power X-raydiffractometry. The bioavailability assessment in Beagle dogs were assayed byLC-MS/MS. It was indicated that wogonin existed in the solid dispersions at amorphousform and that it possibly interacted with PVP K30via hydrogen bond when the ratio ofdrug to the carrier was1:5. Wogonin plasma concentration versus time curve in Beagledogs showed that the solid dispersion approach was associated with a significantdecrease in tmaxand an evident increase in Cmaxcompared to raw substance wogonin.The absolute bioavailability of wogonin solid dispersion was4%, and comparing to rawsubatance wogonin, the relative bioavalability of wogonin in the solid dispersions was679.9%. The major metabolite wogonin-7β-D-glucuronide (W-7-G) in Beagle dogplasma was confirmed by LC/MSn/DAD technology. Comparing to wogonin soliddispersions, the relative bioavalability of arginine-wogonin solution was81.3%. Theconcentration of W-7-G in dog expressed as wogonin equivalent was twelve times tothat of free wogonin in dog plasma, AUC(0-∞)was amplified to thirty times and MRT(0-t)was extended to2.5times.
3. Effects of wogonin administrated by oral on liver microsomal cytochrome P450isoenzyme and mdr1in rats
To evaluate the induction/inhibition action of wogonin on P450isoenzyme andmdr1in rats, the P450content and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b in rat liver after oral administration of wogonin wasanalysed. Male SD rats (n=36) were randomly divided into six groups and givendifferent compounds. P450content in liver microsomes was mearsured by Dual-Beam Spectrophotometric method and mRNA level expression of CYP1A1, CYP2E1,CYP3A1, mdr1a and mdr1b were assayed with RT-PCR. Oral administration ofwogonin at high dose(90mg/kg) can cause significant declined in the content of P450inrat liver, and at low dose(>10mg/kg) can cause decrease significantly in the mRNAlevel expression of CYP1A1.
In the present study, the absorption of features in Caco-2cell and SPIP model ofwogonin and the bioavalability of wogonin solid dispersions and arginine-wogonin inBeagle dogs were investigated, which showed that the oral bioavability of wogonin waslow although it had good absorption characters. The reasons were that it suffered poordissolution and strong second-phase metabolism to produce conjugated metabolitewogonin-7-beta-glucuronide under the action of UDP-glucuronytransferase. It deservesto investigate some bioactive on the conjugated substance. Oral administration ofwogonin at high dose can cause significant difference in the content of P450in rat liver,and all given doses can cause decrease significantly in the mRNA level expression ofCYP1A1, which suggested that liver function should be pay attention during long termtreatment with wogonin and avoid combine with the inhibitor of CYP1A1in clinical.
引文
[1]高中洪,卞曙光.黄芩黄酮对自由基引起的大鼠脑线粒体损伤的保护作用[J].中国药理学通报,2000,(01):81-83.
[2]高中洪,徐辉碧.黄芩黄酮对自由基的清除作用的ESR研究[J].华中理工大学学报,1999,(01):98-100.
[3] Sato T, Kawamoto A, Tamura A, et al. Mechanism of antioxidant action ofpueraria glycoside (PG)-1(an isoflavonoid) and mangiferin (a xanthonoid)[J].Chem Pharm Bull (Tokyo),1992,40(3):721-4.
[4]高中洪,徐辉碧.黄芩黄酮对H_2O_2导致的神经细胞损伤的保护作用[J].中国药理学通报,2000,(05):589-590.
[5] Pal M, Joshi H, Kapoor VP, et al. Antifungal activity of wogonin[J]. PhytotherRes,2003,17(10):1215-6.
[6] Chaudhuri PK, Srivastava R, Kumar S, et al. Phytotoxic and antimicrobialconstituents of Bacopa monnieri and Holmskioldia sanguinea[J]. Phytother Res,2004,18(2):114-7.
[7]胡道道，房喻，马宁，孙作民，曹治权.汉黄芩素与铜（Ⅱ）、钴（Ⅱ）、镍（Ⅱ）固体配合物的合成、表征及抑菌活性研究[J].陕西师大学报(自然科学版),1994,(01):31-34.
[8] Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extractfrom the root of Scutellaria baicalensis and its flavonoids on human gingivalfibroblast[J]. Planta Med,1995,61(2):150-3.
[9] Lin CC, Shieh DE. The anti-inflammatory activity of Scutellaria rivularisextracts and its active components, baicalin, baicalein and wogonin[J]. Am JChin Med,1996,24(1):31-6.
[10] Kim HK, Cheon BS, Kim YH, et al. Effects of naturally occurring flavonoids onnitric oxide production in the macrophage cell line RAW264.7and theirstructure-activity relationships[J]. Biochem Pharmacol,1999,58(5):759-65.
[11] Huang WH, Lee AR, Yang CH. Antioxidative and anti-inflammatory activities ofpolyhydroxyflavonoids of Scutellaria baicalensis GEORGI[J]. Biosci BiotechnolBiochem,2006,70(10):2371-80.
[12] Lim BO, Choue RW, Lee HY, et al. Effect of the flavonoid components obtainedfrom Scutellaria radix on the histamine, immunoglobulin E and lipidperoxidation of spleen lymphocytes of Sprague-Dawley rats[J]. BiosciBiotechnol Biochem,2003,67(5):1126-9.
[13] Chang YL, Shen JJ, Wung BS, et al. Chinese herbal remedy wogonin inhibitsmonocyte chemotactic protein-1gene expression in human endothelial cells[J].Mol Pharmacol,2001,60(3):507-13.
[14] Jang S, Bak EJ, Kim M, et al. Wogonin inhibits osteoclast formation induced bylipopolysaccharide[J]. Phytother Res,2009.
[15] Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E(2)production in macrophages[J]. Eur J Pharmacol,2000,406(3):477-81.
[16] Enomoto R, Suzuki C, Koshiba C, et al. Wogonin prevents immunosuppressiveaction but not anti-inflammatory effect induced by glucocorticoid[J]. Ann N YAcad Sci,2007,1095:412-7.
[17] Nakamura N, Hayasaka S, Zhang XY, et al. Effects of baicalin, baicalein, andwogonin on interleukin-6and interleukin-8expression, and nuclearfactor-kappab binding activities induced by interleukin-1beta in human retinalpigment epithelial cell line[J]. Exp Eye Res,2003,77(2):195-202.
[18] Ma SC, Du J, But PP, et al. Antiviral Chinese medicinal herbs against respiratorysyncytial virus[J]. J Ethnopharmacol,2002,79(2):205-11.
[19] Huang RL, Chen CC, Huang HL, et al. Anti-hepatitis B virus effects of wogoninisolated from Scutellaria baicalensis[J]. Planta Med,2000,66(8):694-8.
[20] Guo Q, Zhao L, You Q, et al. Anti-hepatitis B virus activity of wogonin in vitroand in vivo[J]. Antiviral Res,2007,74(1):16-24.
[21]林红,胡格,索占伟,等.中药有效成分诱导肺微血管内皮细胞表达IFN-γ的研究[J].北京农学院学报,2008,(03):46-49.
[22] Sonoda M, Nishiyama T, Matsukawa Y, et al. Cytotoxic activities of flavonoidsfrom two Scutellaria plants in Chinese medicine[J]. J Ethnopharmacol,2004,91(1):65-8.
[23]王旭光,方琦.汉黄芩素对HL-60细胞端粒酶活性的影响[J].四川医学,2004,(08):854-855.
[24] Zhang HW, Yang Y, Zhang K, et al. Wogonin induced differentiation and G1phase arrest of human U-937leukemia cells via PKCdelta phosphorylation[J].Eur J Pharmacol,2008,591(1-3):7-12.
[25] Zhang K, Guo QL, You QD, et al. Wogonin induces the granulocyticdifferentiation of human NB4promyelocytic leukemia cells and up-regulatesphospholipid scramblase1gene expression[J]. Cancer Sci,2008,99(4):689-95.
[26] Nou-Ying Tang CS, Chung GCaJ. Wogonin inhibits WEHI-3leukemia cells inBlab/C mice In Vivo[J]. The FASEB Journal,2007,21:728-15.
[27] Himeji M, Ohtsuki T, Fukazawa H, et al. Difference of growth-inhibitory effectof Scutellaria baicalensis-producing flavonoid wogonin among human cancercells and normal diploid cell[J]. Cancer Lett,2007,245(1-2):269-74.
[28] Wang W, Guo QL, You QD, et al. The Anticancer Activities of Wogonin inMurine Sarcoma S180both in Vitro and in Vivo[J]. Biol Pharm Bull,2006,29(6):1132-7.
[29]陈新美,贾强.汉黄芩素体外抗骨肉瘤作用的研究[J].中国药房,2009,(36):2813-2814.
[30]黎丹戎,张玮.汉黄芩素诱导人卵巢癌细胞A2780凋亡及对细胞端粒酶活性的影响[J].癌症,2003,(08):801-805.
[31]张汉英,黎丹戎,李力,等.汉黄芩素对移植人卵巢癌SKOV3细胞裸鼠组织端粒酶蛋白hTERT影响与凋亡相关性研究[J].时珍国医国药,2008,(08):1987-1989.
[32] Lu N, Gao Y, Ling Y, et al. Wogonin suppresses tumor growth in vivo andVEGF-induced angiogenesis through inhibiting tyrosine phosphorylation ofVEGFR2[J]. Life Sci,2008,82(17-18):956-63.
[33] Wang W, Guo Q, You Q, et al. Involvement of bax/bcl-2in wogonin-inducedapoptosis of human hepatoma cell line SMMC-7721[J]. Anticancer Drugs,2006,17(7):797-805.
[34] Ikemoto S, Sugimura K, Yoshida N, et al. Antitumor effects of Scutellariae radixand its components baicalein, baicalin, and wogonin on bladder cancer celllines[J]. Urology,2000,55(6):951-5.
[35] Bonham M, Posakony J, Coleman I, et al. Characterization of chemicalconstituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitoryactivities toward prostate carcinoma[J]. Clin Cancer Res,2005,11(10):3905-14.
[36] Cho J, Lee HK. Wogonin inhibits ischemic brain injury in a rat model ofpermanent middle cerebral artery occlusion[J]. Biol Pharm Bull,2004,27(10):1561-4.
[37] Lee H, Kim YO, Kim H, et al. Flavonoid wogonin from medicinal herb isneuroprotective by inhibiting inflammatory activation of microglia[J]. FASEB J,2003,17(13):1943-4.
[38] Piao HZ, Choi IY, Park JS, et al. Wogonin inhibits microglial cell migration viasuppression of nuclear factor-kappa B activity[J]. Int Immunopharmacol,2008,8(12):1658-62.
[39]朴花子,于兆霞,朴日龙,等.汉黄芩素对脂多糖诱导一氧化氮和单核细胞趋化蛋白-1的影响[J].中药药理与临床,2007,(03):20-21.
[40]朴花子,崔弘,朴日龙,等.汉黄芩素对脂多糖诱导的促炎性因子的影响[J].西安交通大学学报(医学版),2008,(02):230-232.
[41]朴花子,郑善子,崔万善.汉黄芩素对脂多糖诱导细胞因子IL-6和趋化因子RANTES的影响[J].中药药理与临床,2008,(06):34-36.
[42] Venkatesh G, Ramanathan S, Nair NK, et al. Permeability of atenolol andpropranolol in the presence of dimethyl sulfoxide in rat single-pass intestinalperfusion assay with liquid chromatography/UV detection[J]. BiomedChromatogr,2007,21(5):484-90.
[43] Dackson K, Stone JA, Palin KJ, et al. Evaluation of the mass balanceassumption with respect to the two-resistance model of intestinal absorption byusing in situ single-pass intestinal perfusion of theophylline in rats[J]. J PharmSci,1992,81(4):321-5.
[44] Raoof AA, Butler J, Devane JG. Assessment of regional differences in intestinalfluid movement in the rat using a modified in situ single pass perfusion model[J].Pharm Res,1998,15(8):1314-6.
[45] Crowe A, Lemaire M. In vitro and in situ absorption of SDZ-RAD using ahuman intestinal cell line (Caco-2) and a single pass perfusion model in rats:comparison with rapamycin[J]. Pharm Res,1998,15(11):1666-72.
[46] Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenolred, and14C-PEG-3350methods to determine water absorption in the ratsingle-pass intestinal perfusion model[J]. AAPS PharmSci,2001,3(3):E25.
[47] Sutton SC, Rinaldi MT, McCarthy JM, et al. A statistical method for thedetermination of absorption rate constant estimated using the rat single passintestinal perfusion model and multiple linear regression[J]. J Pharm Sci,2002,91(4):1046-53.
[48] McLeod BJ, Zhang H, Huang L, et al. An in situ single-pass perfusion model forassessing absorption across the intestinal mucosa of the brushtail possum[J]. N ZVet J,2005,53(4):234-41.
[49] Boerner P, Evans-Laying M, U HS, et al. Polarity of neutral amino acid transportand characterization of a broad specificity transport activity in a kidneyepithelial cell line, MDCK[J]. J Biol Chem,1986,261(30):13957-62.
[50] Veronesi B. Characterization of the MDCK cell line for screeningneurotoxicants[J]. Neurotoxicology,1996,17(2):433-43.
[51] Karyekar CS, Eddington ND, Garimella TS, et al. Evaluation ofP-glycoprotein-mediated renal drug interactions in an MDR1-MDCK model[J].Pharmacotherapy,2003,23(4):436-42.
[52] Yang B, Lv Y, Chen Y, et al. Inhibitory action of soybean beta-conglycininhydrolysates on Salmonella typhimurium translocation in Caco-2epithelial cellmonolayers[J]. J Agric Food Chem,2008,56(16):7522-7.
[53] Zegura B, Volcic M, Lah TT, et al. Different sensitivities of human colonadenocarcinoma (CaCo-2), astrocytoma (IPDDC-A2) and lymphoblastoid(NCNC) cell lines to microcystin-LR induced reactive oxygen species and DNAdamage[J]. Toxicon,2008,52(3):518-25.
[54] Siissalo S, Zhang H, Stilgenbauer E, et al. The expression of mostUDP-glucuronosyltransferases (UGTs) is increased significantly during Caco-2cell differentiation, whereas UGT1A6is highly expressed also inundifferentiated cells[J]. Drug Metab Dispos,2008,36(11):2331-6.
[55] Mahler GJ, Shuler ML, Glahn RP. Characterization of Caco-2and HT29-MTXcocultures in an in vitro digestion/cell culture model used to predict ironbioavailability[J]. J Nutr Biochem,2009,20(7):494-502.
[56] Dai JY, Yang JL, Li C. Transport and metabolism of flavonoids from Chineseherbal remedy Xiaochaihu-tang across human intestinal Caco-2cellmonolayers[J]. Acta Pharmacol Sin,2008,29(9):1086-93.
[57] Yamada T, Saito N, Anraku M, et al. Physicochemical characterization of a newcrystal form and improvements in the pharmaceutical properties of the poorlywater-soluble antiosteoporosis drug3,9-bis(N,N-dimethylcarbamoy-loxy)-5H-benzofuro[3,2-c]quinoline-6-one(KCA-098) by solid dispersion with hydroxypropylcellulose[J]. Pharm DevTechnol,2000,5(4):443-54.
[58] Li YP, Zhang XY, Zhou JJ, et al. Preparation and dissolution property ofipriflavone solid dispersion[J]. Zhongguo Yao Li Xue Bao,1999,20(10):957-60.
[59] Xiao HB, Krucker M, Albert K, et al. Determination and identification ofisoflavonoids in Radix astragali by matrix solid-phase dispersion extraction andhigh-performance liquid chromatography with photodiode array and massspectrometric detection[J]. J Chromatogr A,2004,1032(1-2):117-24.
[60] Manhita AC, Teixeira DM, da CCT. Application of sample disruption methods inthe extraction of anthocyanins from solid or semi-solid vegetable samples[J]. JChromatogr A,2006,1129(1):14-20.
[61] Kwon SH, Kim SY, Ha KW, et al. Pharmaceutical evaluation of genistein-loadedpluronic micelles for oral delivery[J]. Arch Pharm Res,2007,30(9):1138-43.
[62] Sun N, Zhang X, Lu Y, et al. In vitro evaluation and pharmacokinetics in dogs ofsolid dispersion pellets containing Silybum marianum extract prepared byfluid-bed coating[J]. Planta Med,2008,74(2):126-32.
[63]杜玥,杨汉煜.液相色谱串联质谱法测定大鼠血浆中的汉黄芩素[J].药学学报,2002,(05):362-366.
[64]崔福德.药剂学（第5版）[M].人民卫生出版社,2007:1.
[65] Wrighton SA, Stevens JC. The human hepatic cytochromes P450involved indrug metabolism[J]. Crit Rev Toxicol,1992,22(1):1-21.
[66] Role of Drug Metabolism and Pharmacokinetics in Toxicologic Pathology.Proceedings of the13th International Symposium of the Society of ToxicologicPathologists. Charleston, South Carolina, June5-9,1994[J]. Toxicol Pathol,1995,23(2):97-234.
[67] Alavijeh MS, Palmer AM. The pivotal role of drug metabolism andpharmacokinetics in the discovery and development of new medicines[J].IDrugs,2004,7(8):755-63.
[68] Hsieh Y, Cheng KC, Wang Y, et al. The role of exploratory drug metabolism andpharmacokinetics in new drug research: case study-selection of a thrombinreceptor antagonist for development[J]. Curr Pharm Des,2009,15(19):2262-9.
[69] Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring inassociation with terfenadine use[J]. JAMA,1990,264(21):2788-90.
[70] Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoproteinand cytochrome P4503A coordinately up-regulate these proteins in human coloncarcinoma cells[J]. Mol Pharmacol,1996,49(2):311-8.
[71] Lo A, Burckart GJ. P-glycoprotein and drug therapy in organ transplantation[J].J Clin Pharmacol,1999,39(10):995-1005.
[72] Konishi Y, Hagiwara K, Shimizu M. Transepithelial transport of fluorescein inCaco-2cell monolayers and use of such transport in in vitro evaluation ofphenolic acid availability[J]. Biosci Biotechnol Biochem,2002,66(11):2449-57.
[73] Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir: effects on P-glycoproteintransport and CYP3A metabolism in vitro[J]. Drug Metab Dispos,2005,33(6):764-70.
[74] Luo FR, Paranjpe PV, Guo A, et al. Intestinal transport of irinotecan in Caco-2cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, andMRP1[J]. Drug Metab Dispos,2002,30(7):763-70.
[75] Tep J, Videmann B, Mazallon M, et al. Transepithelial transport of fusariotoxinnivalenol: mediation of secretion by ABC transporters[J]. Toxicol Lett,2007,170(3):248-58.
[76] Jia JX, Wasan KM. Effects of monoglycerides on rhodamine123accumulation,estradiol17beta-D-glucuronide bidirectional transport and MRP2proteinexpression within Caco-2cells[J]. J Pharm Pharm Sci,2008,11(3):45-62.
[77] Fujimoto H, Higuchi M, Watanabe H, et al. P-glycoprotein mediates effluxtransport of darunavir in human intestinal Caco-2and ABCB1gene-transfectedrenal LLC-PK1cell lines[J]. Biol Pharm Bull,2009,32(9):1588-93.
[78] Yee S. In vitro permeability across Caco-2cells (colonic) can predict in vivo(small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997,14(6):763-6.
[79] Krishna G, Chen K, Lin C, et al. Permeability of lipophilic compounds in drugdiscovery using in-vitro human absorption model, Caco-2[J]. Int J Pharm,2001,222(1):77-89.
[80] Fagerholm U. Prediction of human pharmacokinetics--gastrointestinalabsorption[J]. J Pharm Pharmacol,2007,59(7):905-16.
[81] Ruckert P, Bates SR, Fisher AB. Role of clathrin-and actin-dependentendocytotic pathways in lung phospholipid uptake[J]. Am J Physiol Lung CellMol Physiol,2003,284(6):L981-9.
[82]谢海棠,赵小辰. Caco-2细胞对人参皂苷Rg3的摄取及代谢研究[J].中国临床药理学与治疗学,2004,(03):257-260.
[83] Brunet JL, Maresca M, Fantini J, et al. Human intestinal absorption ofimidacloprid with Caco-2cells as enterocyte model[J]. Toxicol Appl Pharmacol,2004,194(1):1-9.
[84] Artursson P, Palm K, Luthman K. Caco-2monolayers in experimental andtheoretical predictions of drug transport[J]. Adv Drug Deliv Rev,2001,46(1-3):27-43.
[85] Yamashita S, Furubayashi T, Kataoka M, et al. Optimized conditions forprediction of intestinal drug permeability using Caco-2cells[J]. Eur J Pharm Sci,2000,10(3):195-204.
[86]杨秀伟,杨晓达,王莹,等.中药化学成分肠吸收研究中Caco-2细胞模型和标准操作规程的建立[J].中西医结合学报,2007,(06):634-641.
[87]张志宏,聂淑芳,王启明,等.双嘧达莫大鼠在体胃、肠吸收动力学研究[J].中国药学杂志,2009,(16):1229-1233.
[88]关颖,杨涛,崔福德,等.运用单向灌流模型研究抗糖尿病创新药物西格列松大鼠在体肠的吸收[J].沈阳药科大学学报,2006,(08):483-487.
[89] You J, Li QP, Yu YW, et al.[Absorption of zedoary oil in rat intestine using insitu single pass perfusion model][J]. Yao Xue Xue Bao,2004,39(10):849-53.
[90] Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenolred, and14C-PEG-3350methods to determine water absorption in the ratsingle-pass intestinal perfusion model[J]. AAPS PharmSci,2001,3(3):E25.
[91]胡一桥，钱陈钦，郑梁元，郁伟海，谭仁祥. Intestinal absorption of cefiximein rats[J]. Acta Pharmacologica Sinica,1999,(01):54-57.
[92]朱玲玲,李娟,王广基.地西泮的大鼠在体肠吸收机理研究[J].中国药科大学学报,2006,(06):507-511.
[93] Artursson P, Magnusson C. Epithelial transport of drugs in cell culture. II: Effectof extracellular calcium concentration on the paracellular transport of drugs ofdifferent lipophilicities across monolayers of intestinal epithelial (Caco-2)cells[J]. J Pharm Sci,1990,79(7):595-600.
[94] Fagerholm U, Johansson M, Lennernas H. Comparison between permeabilitycoefficients in rat and human jejunum[J]. Pharm Res,1996,13(9):1336-42.
[95] US Food and Drug Administration, Guidance for Industry, Bioanalytical MethodValidation, Centre for Drug Evaluation and Research (CDER), Rockville,2001[J].
[96] Chen X, Wang H, Du Y, et al. Quantitation of the flavonoid wogonin and itsmajor metabolite wogonin-7beta-D-glucuronide in rat plasma by liquidchromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt TechnolBiomed Life Sci,2002,775(2):169-78.
[97] Tsai TH, Chou CJ, Tsai TR, et al. Determination of wogonin in rat plasma byliquid chromatography and its pharmacokinetic application[J]. Planta Med,1996,62(3):263-6.
[98]许颖,柯学,平其能. HPLC法测定大鼠静脉注射汉黄芩素的血药浓度及其药动学研究[J].药学与临床研究,2007,(01):35-38.
[99] Zuo F, Zhou ZM, Zhang Q, et al. Pharmacokinetic study on themulti-constituents of Huangqin-Tang decoction in rats[J]. Biol Pharm Bull,2003,26(7):911-9.
[100] Du Y, Chen XY, Yang HY, et al.[Determination of wogonin in rat plasma byliquid chromatography-tandem mass spectrometry][J]. Yao Xue Xue Bao,2002,37(5):362-6.
[101] Tsai TH, Chou CJ, Tsai TR, et al. Determination of wogonin in rat plasma byliquid chromatography and its pharmacokinetic application[J]. Planta Med,1996,62(3):263-6.
[102] Peng J, Qi Q, You Q, et al. Subchronic toxicity and plasma pharmacokineticstudies on wogonin, a natural flavonoid, in Beagle dogs[J]. J Ethnopharmacol,2009,124(2):257-62.
[103] Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of itsmetabolism, pharmacokinetics and drug interactions[J]. Clin Pharmacokinet,2005,44(5):467-94.
[104] Kuntzman R, Levin W, Jacobson M, et al. Studies on microsomal hydroxylationand the demonstration of a new carbon monoxide binding pigment in livermicrosomes[J]. Life Sci II,1968,7(4):215-24.
[105] Morris DL, Davila JC. Analysis of rat cytochrome P450isoenzyme expressionusing semi-quantitative reverse transcriptase-polymerase chain reaction(RT-PCR)[J]. Biochem Pharmacol,1996,52(5):781-92.
[106] Schott B, Bennis S, Pourquier P, et al. Differential over-expression of mdr1genes in multidrug-resistant rat glioblastoma cell lines selected with doxorubicinor vincristine[J]. Int J Cancer,1993,55(1):115-21.
[107] Quinn AM, Penning TM. Comparisons of(+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol activation by human cytochromeP450and aldo-keto reductase enzymes: effect of redox state and expressionlevels[J]. Chem Res Toxicol,2008,21(5):1086-94.
[108] Koop DR. Oxidative and reductive metabolism by cytochrome P4502E1[J].FASEB J,1992,6(2):724-30.
[1]陈翠丽,徐广飞,顾海鹰,纪康,蒲明亮.黄芩中汉黄芩素的提取研究.交通医学.2008.(02):128-129.
[2]喻春皓,张萍,王宏志.纤维素酶辅助提取生黄芩饮片中黄酮苷元的工艺研究.安徽农业科学.2009.(35):17692-17694+17697.
[3]高中洪,卞曙光.黄芩黄酮对自由基引起的大鼠脑线粒体损伤的保护作用.中国药理学通报.2000.(01):81-83.
[4]高中洪,徐辉碧.黄芩黄酮对自由基的清除作用的ESR研究.华中理工大学学报.1999.(01):98-100.
[5] Sato T, Kawamoto A, Tamura A, Tatsumi Y, Fujii T. Mechanism of antioxidantaction of pueraria glycoside (PG)-1(an isoflavonoid) and mangiferin (axanthonoid). Chem Pharm Bull (Tokyo).1992.40(3):721-4.
[6]高中洪,徐辉碧.黄芩黄酮对H_2O_2导致的神经细胞损伤的保护作用.中国药理学通报.2000.(05):589-590.
[7] Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extractfrom the root of Scutellaria baicalensis and its flavonoids on human gingivalfibroblast. Planta Med.1995.61(2):150-3.
[8] Lin CC, Shieh DE. The anti-inflammatory activity of Scutellaria rivularisextracts and its active components, baicalin, baicalein and wogonin. Am J ChinMed.1996.24(1):31-6.
[9] Kim HK, Cheon BS, Kim YH, Kim SY, Kim HP. Effects of naturally occurringflavonoids on nitric oxide production in the macrophage cell line RAW264.7and their structure-activity relationships. Biochem Pharmacol.1999.58(5):759-65.
[10] Huang WH, Lee AR, Yang CH. Antioxidative and anti-inflammatory activities ofpolyhydroxyflavonoids of Scutellaria baicalensis GEORGI. Biosci BiotechnolBiochem.2006.70(10):2371-80.
[11] Lim BO, Choue RW, Lee HY, Seong NS, Kim JD. Effect of the flavonoidcomponents obtained from Scutellaria radix on the histamine, immunoglobulinE and lipid peroxidation of spleen lymphocytes of Sprague-Dawley rats. BiosciBiotechnol Biochem.2003.67(5):1126-9.
[12] Chang YL, Shen JJ, Wung BS, Cheng JJ, Wang DL. Chinese herbal remedywogonin inhibits monocyte chemotactic protein-1gene expression in humanendothelial cells. Mol Pharmacol.2001.60(3):507-13.
[13] Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E(2)production in macrophages. Eur J Pharmacol.2000.406(3):477-81.
[14] Jang S, Bak EJ, Kim M, et al. Wogonin inhibits osteoclast formation induced bylipopolysaccharide. Phytother Res.2009.
[15] Nakamura N, Hayasaka S, Zhang XY, et al. Effects of baicalin, baicalein, andwogonin on interleukin-6and interleukin-8expression, and nuclearfactor-kappab binding activities induced by interleukin-1beta in human retinalpigment epithelial cell line. Exp Eye Res.2003.77(2):195-202.
[16] Heo HJ, Lee HJ, Kim YS, et al. Effects of baicalin and wogonin on mucinrelease from cultured airway epithelial cells. Phytother Res.2007.21(12):1130-4.
[17] Enomoto R, Suzuki C, Koshiba C, et al. Wogonin prevents immunosuppressiveaction but not anti-inflammatory effect induced by glucocorticoid. Ann N YAcad Sci.2007.1095:412-7.
[18] Pal M, Joshi H, Kapoor VP, Pushpangadan P, Chaurasia L. Antifungal activity ofwogonin. Phytother Res.2003.17(10):1215-6.
[19] Chaudhuri PK, Srivastava R, Kumar S, Kumar S. Phytotoxic and antimicrobialconstituents of Bacopa monnieri and Holmskioldia sanguinea. Phytother Res.2004.18(2):114-7.
[20]胡道道，房喻，马宁，孙作民，曹治权.汉黄芩素与铜（Ⅱ）、钴（Ⅱ）、镍（Ⅱ）固体配合物的合成、表征及抑菌活性研究.陕西师大学报(自然科学版).1994.(01):31-34.
[21] Ma SC, Du J, But PP, et al. Antiviral Chinese medicinal herbs against respiratorysyncytial virus. J Ethnopharmacol.2002.79(2):205-11.
[22] Huang RL, Chen CC, Huang HL, et al. Anti-hepatitis B virus effects of wogoninisolated from Scutellaria baicalensis. Planta Med.2000.66(8):694-8.
[23] Guo Q, Zhao L, You Q, et al. Anti-hepatitis B virus activity of wogonin in vitroand in vivo. Antiviral Res.2007.74(1):16-24.
[24]林红,胡格,索占伟,伊鹏霏,胡屹屹,穆祥.中药有效成分诱导肺微血管内皮细胞表达IFN-γ的研究.北京农学院学报.2008.(03):46-49.
[25] Sonoda M, Nishiyama T, Matsukawa Y, Moriyasu M. Cytotoxic activities offlavonoids from two Scutellaria plants in Chinese medicine. J Ethnopharmacol.2004.91(1):65-8.
[26]王旭光,方琦.汉黄芩素对HL-60细胞端粒酶活性的影响.四川医学.2004.(08):854-855.
[27] Zhang HW, Yang Y, Zhang K, et al. Wogonin induced differentiation and G1phase arrest of human U-937leukemia cells via PKCdelta phosphorylation. EurJ Pharmacol.2008.591(1-3):7-12.
[28] Zhang K, Guo QL, You QD, et al. Wogonin induces the granulocyticdifferentiation of human NB4promyelocytic leukemia cells and up-regulatesphospholipid scramblase1gene expression. Cancer Sci.2008.99(4):689-95.
[29] Nou-Ying Tang CS, Chung GCaJ. Wogonin inhibits WEHI-3leukemia cells inBlab/C mice In Vivo. The FASEB Journal.2007.21:728-15.
[30] Himeji M, Ohtsuki T, Fukazawa H, et al. Difference of growth-inhibitory effectof Scutellaria baicalensis-producing flavonoid wogonin among human cancercells and normal diploid cell. Cancer Lett.2007.245(1-2):269-74.
[31]陈新美,贾强.汉黄芩素体外抗骨肉瘤作用的研究.中国药房.2009.(36):2813-2814.
[32] Wang W, Guo QL, You QD, et al. The Anticancer Activities of Wogonin inMurine Sarcoma S180both in Vitro and in Vivo. Biol Pharm Bull.2006.29(6):1132-7.
[33]黎丹戎,张玮.汉黄芩素诱导人卵巢癌细胞A2780凋亡及对细胞端粒酶活性的影响.癌症.2003.(08):801-805.
[34]张汉英,黎丹戎,李力,张玮.汉黄芩素对移植人卵巢癌SKOV3细胞裸鼠组织端粒酶蛋白hTERT影响与凋亡相关性研究.时珍国医国药.2008.(08):1987-1989.
[35] Lu N, Gao Y, Ling Y, et al. Wogonin suppresses tumor growth in vivo andVEGF-induced angiogenesis through inhibiting tyrosine phosphorylation ofVEGFR2. Life Sci.2008.82(17-18):956-63.
[36] Wang W, Guo Q, You Q, et al. Involvement of bax/bcl-2in wogonin-inducedapoptosis of human hepatoma cell line SMMC-7721. Anticancer Drugs.2006.17(7):797-805.
[37] Ikemoto S, Sugimura K, Yoshida N, et al. Antitumor effects of Scutellariae radixand its components baicalein, baicalin, and wogonin on bladder cancer cell lines.Urology.2000.55(6):951-5.
[38] Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson PS.Characterization of chemical constituents in Scutellaria baicalensis withantiandrogenic and growth-inhibitory activities toward prostate carcinoma. ClinCancer Res.2005.11(10):3905-14.
[39] Cho J, Lee HK. Wogonin inhibits ischemic brain injury in a rat model ofpermanent middle cerebral artery occlusion. Biol Pharm Bull.2004.27(10):1561-4.
[40] Lee H, Kim YO, Kim H, et al. Flavonoid wogonin from medicinal herb isneuroprotective by inhibiting inflammatory activation of microglia. FASEB J.2003.17(13):1943-4.
[41] Piao HZ, Choi IY, Park JS, et al. Wogonin inhibits microglial cell migration viasuppression of nuclear factor-kappa B activity. Int Immunopharmacol.2008.8(12):1658-62.
[42]朴花子,于兆霞,朴日龙,李迎军.汉黄芩素对脂多糖诱导一氧化氮和单核细胞趋化蛋白-1的影响.中药药理与临床.2007.(03):20-21.
[43]朴花子,崔弘,朴日龙,李迎军.汉黄芩素对脂多糖诱导的促炎性因子的影响.西安交通大学学报(医学版).2008.(02):230-232.
[44]朴花子,郑善子,崔万善.汉黄芩素对脂多糖诱导细胞因子IL-6和趋化因子RANTES的影响.中药药理与临床.2008.(06):34-36.
[45] Park HG, Yoon SY, Choi JY, et al. Anticonvulsant effect of wogonin isolatedfrom Scutellaria baicalensis. Eur J Pharmacol.2007.574(2-3):112-9.
[46] Hui KM, Huen MS, Wang HY, et al. Anxiolytic effect of wogonin, abenzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi.Biochem Pharmacol.2002.64(9):1415-24.
[47] Kong EK, Huang Y, Sanderson JE, Chan KB, Yu S, Yu CM. Baicalein andWogonin inhibit collagen deposition in SHR and WKY cardiac fibroblastcultures. BMB Rep.2010.43(4):297-303.
[48] Lin CM, Chang H, Chen YH, Li SY, Wu IH, Chiu JH. Protective role ofwogonin against lipopolysaccharide-induced angiogenesis via VEGFR-2, notVEGFR-1. Int Immunopharmacol.2006.6(11):1690-8.
[49]王立明，张如松，方瑞英，葛文再.黄芩有效成分对四氯化碳致伤的原代培养大鼠肝细胞的作用.浙江医科大学学报.1996.(06):241-244.
[50] Qi Q, Peng J, Liu W, et al. Toxicological studies of wogonin in experimentalanimals. Phytother Res.2009.23(3):417-22.
[51] Peng J, Qi Q, You Q, et al. Subchronic toxicity and plasma pharmacokineticstudies on wogonin, a natural flavonoid, in Beagle dogs. J Ethnopharmacol.2009.124(2):257-62.
[52]许颖,柯学,平其能. HPLC法测定大鼠静脉注射汉黄芩素的血药浓度及其药动学研究.药学与临床研究.2007.(01):35-38.
[53]杜玥,杨汉煜.液相色谱串联质谱法测定大鼠血浆中的汉黄芩素.药学学报.2002.(05):362-366.
[54] Chen X, Wang H, Du Y, Zhong D. Quantitation of the flavonoid wogonin and itsmajor metabolite wogonin-7beta-D-glucuronide in rat plasma by liquidchromatography-tandem mass spectrometry. J Chromatogr B Analyt TechnolBiomed Life Sci.2002.775(2):169-78.
[55]柯学,许颖,严菲,平其能.汉黄芩素脂质体的制备及大鼠体内药代动力学.中国药科大学学报.2007.(06):502-506.
[56]徐倩,邓丹丹,曹志娟,谢琼,梁建英,卢建忠.荧光法和分子对接研究4种黄酮与血清白蛋白的相互作用.分析化学.2010.(04):483-487.
[57] Tian J, Liu J, Xie J, Yao X, Hu Z, Chen X. Binding of wogonin to human serumalbumin: a common binding site of wogonin in subdomain IIA. J PhotochemPhotobiol B.2004.74(1):39-45.
[58] Liu Y, He W, Gao W, Hu Z, Chen X. Binding of wogonin to humangammaglobulin. Int J Biol Macromol.2005.37(1-2):1-11.
[59] Lin YT, Hsiu SL, Hou YC, Chen HY, Chao PD. Degradation of flavonoidaglycones by rabbit, rat and human fecal flora. Biol Pharm Bull.2003.26(5):747-51.
[60] Kim BR, Kim DH, Park R, et al. Effect of an extract of the root of Scutellariabaicalensis and its flavonoids on aflatoxin B1oxidizing cytochrome P450enzymes. Planta Med.2001.67(5):396-9.
[61] Si D, Wang Y, Zhou YH, et al. Mechanism of CYP2C9inhibition by flavonesand flavonols. Drug Metab Dispos.2009.37(3):629-34.
[2]高中洪,徐辉碧.黄芩黄酮对自由基的清除作用的ESR研究[J].华中理工大学学报,1999,(01):98-100.
[3] Sato T, Kawamoto A, Tamura A, et al. Mechanism of antioxidant action ofpueraria glycoside (PG)-1(an isoflavonoid) and mangiferin (a xanthonoid)[J].Chem Pharm Bull (Tokyo),1992,40(3):721-4.
[4]高中洪,徐辉碧.黄芩黄酮对H_2O_2导致的神经细胞损伤的保护作用[J].中国药理学通报,2000,(05):589-590.
[5] Pal M, Joshi H, Kapoor VP, et al. Antifungal activity of wogonin[J]. PhytotherRes,2003,17(10):1215-6.
[6] Chaudhuri PK, Srivastava R, Kumar S, et al. Phytotoxic and antimicrobialconstituents of Bacopa monnieri and Holmskioldia sanguinea[J]. Phytother Res,2004,18(2):114-7.
[7]胡道道，房喻，马宁，孙作民，曹治权.汉黄芩素与铜（Ⅱ）、钴（Ⅱ）、镍（Ⅱ）固体配合物的合成、表征及抑菌活性研究[J].陕西师大学报(自然科学版),1994,(01):31-34.
[8] Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extractfrom the root of Scutellaria baicalensis and its flavonoids on human gingivalfibroblast[J]. Planta Med,1995,61(2):150-3.
[9] Lin CC, Shieh DE. The anti-inflammatory activity of Scutellaria rivularisextracts and its active components, baicalin, baicalein and wogonin[J]. Am JChin Med,1996,24(1):31-6.
[10] Kim HK, Cheon BS, Kim YH, et al. Effects of naturally occurring flavonoids onnitric oxide production in the macrophage cell line RAW264.7and theirstructure-activity relationships[J]. Biochem Pharmacol,1999,58(5):759-65.
[11] Huang WH, Lee AR, Yang CH. Antioxidative and anti-inflammatory activities ofpolyhydroxyflavonoids of Scutellaria baicalensis GEORGI[J]. Biosci BiotechnolBiochem,2006,70(10):2371-80.
[12] Lim BO, Choue RW, Lee HY, et al. Effect of the flavonoid components obtainedfrom Scutellaria radix on the histamine, immunoglobulin E and lipidperoxidation of spleen lymphocytes of Sprague-Dawley rats[J]. BiosciBiotechnol Biochem,2003,67(5):1126-9.
[13] Chang YL, Shen JJ, Wung BS, et al. Chinese herbal remedy wogonin inhibitsmonocyte chemotactic protein-1gene expression in human endothelial cells[J].Mol Pharmacol,2001,60(3):507-13.
[14] Jang S, Bak EJ, Kim M, et al. Wogonin inhibits osteoclast formation induced bylipopolysaccharide[J]. Phytother Res,2009.
[15] Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E(2)production in macrophages[J]. Eur J Pharmacol,2000,406(3):477-81.
[16] Enomoto R, Suzuki C, Koshiba C, et al. Wogonin prevents immunosuppressiveaction but not anti-inflammatory effect induced by glucocorticoid[J]. Ann N YAcad Sci,2007,1095:412-7.
[17] Nakamura N, Hayasaka S, Zhang XY, et al. Effects of baicalin, baicalein, andwogonin on interleukin-6and interleukin-8expression, and nuclearfactor-kappab binding activities induced by interleukin-1beta in human retinalpigment epithelial cell line[J]. Exp Eye Res,2003,77(2):195-202.
[18] Ma SC, Du J, But PP, et al. Antiviral Chinese medicinal herbs against respiratorysyncytial virus[J]. J Ethnopharmacol,2002,79(2):205-11.
[19] Huang RL, Chen CC, Huang HL, et al. Anti-hepatitis B virus effects of wogoninisolated from Scutellaria baicalensis[J]. Planta Med,2000,66(8):694-8.
[20] Guo Q, Zhao L, You Q, et al. Anti-hepatitis B virus activity of wogonin in vitroand in vivo[J]. Antiviral Res,2007,74(1):16-24.
[21]林红,胡格,索占伟,等.中药有效成分诱导肺微血管内皮细胞表达IFN-γ的研究[J].北京农学院学报,2008,(03):46-49.
[22] Sonoda M, Nishiyama T, Matsukawa Y, et al. Cytotoxic activities of flavonoidsfrom two Scutellaria plants in Chinese medicine[J]. J Ethnopharmacol,2004,91(1):65-8.
[23]王旭光,方琦.汉黄芩素对HL-60细胞端粒酶活性的影响[J].四川医学,2004,(08):854-855.
[24] Zhang HW, Yang Y, Zhang K, et al. Wogonin induced differentiation and G1phase arrest of human U-937leukemia cells via PKCdelta phosphorylation[J].Eur J Pharmacol,2008,591(1-3):7-12.
[25] Zhang K, Guo QL, You QD, et al. Wogonin induces the granulocyticdifferentiation of human NB4promyelocytic leukemia cells and up-regulatesphospholipid scramblase1gene expression[J]. Cancer Sci,2008,99(4):689-95.
[26] Nou-Ying Tang CS, Chung GCaJ. Wogonin inhibits WEHI-3leukemia cells inBlab/C mice In Vivo[J]. The FASEB Journal,2007,21:728-15.
[27] Himeji M, Ohtsuki T, Fukazawa H, et al. Difference of growth-inhibitory effectof Scutellaria baicalensis-producing flavonoid wogonin among human cancercells and normal diploid cell[J]. Cancer Lett,2007,245(1-2):269-74.
[28] Wang W, Guo QL, You QD, et al. The Anticancer Activities of Wogonin inMurine Sarcoma S180both in Vitro and in Vivo[J]. Biol Pharm Bull,2006,29(6):1132-7.
[29]陈新美,贾强.汉黄芩素体外抗骨肉瘤作用的研究[J].中国药房,2009,(36):2813-2814.
[30]黎丹戎,张玮.汉黄芩素诱导人卵巢癌细胞A2780凋亡及对细胞端粒酶活性的影响[J].癌症,2003,(08):801-805.
[31]张汉英,黎丹戎,李力,等.汉黄芩素对移植人卵巢癌SKOV3细胞裸鼠组织端粒酶蛋白hTERT影响与凋亡相关性研究[J].时珍国医国药,2008,(08):1987-1989.
[32] Lu N, Gao Y, Ling Y, et al. Wogonin suppresses tumor growth in vivo andVEGF-induced angiogenesis through inhibiting tyrosine phosphorylation ofVEGFR2[J]. Life Sci,2008,82(17-18):956-63.
[33] Wang W, Guo Q, You Q, et al. Involvement of bax/bcl-2in wogonin-inducedapoptosis of human hepatoma cell line SMMC-7721[J]. Anticancer Drugs,2006,17(7):797-805.
[34] Ikemoto S, Sugimura K, Yoshida N, et al. Antitumor effects of Scutellariae radixand its components baicalein, baicalin, and wogonin on bladder cancer celllines[J]. Urology,2000,55(6):951-5.
[35] Bonham M, Posakony J, Coleman I, et al. Characterization of chemicalconstituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitoryactivities toward prostate carcinoma[J]. Clin Cancer Res,2005,11(10):3905-14.
[36] Cho J, Lee HK. Wogonin inhibits ischemic brain injury in a rat model ofpermanent middle cerebral artery occlusion[J]. Biol Pharm Bull,2004,27(10):1561-4.
[37] Lee H, Kim YO, Kim H, et al. Flavonoid wogonin from medicinal herb isneuroprotective by inhibiting inflammatory activation of microglia[J]. FASEB J,2003,17(13):1943-4.
[38] Piao HZ, Choi IY, Park JS, et al. Wogonin inhibits microglial cell migration viasuppression of nuclear factor-kappa B activity[J]. Int Immunopharmacol,2008,8(12):1658-62.
[39]朴花子,于兆霞,朴日龙,等.汉黄芩素对脂多糖诱导一氧化氮和单核细胞趋化蛋白-1的影响[J].中药药理与临床,2007,(03):20-21.
[40]朴花子,崔弘,朴日龙,等.汉黄芩素对脂多糖诱导的促炎性因子的影响[J].西安交通大学学报(医学版),2008,(02):230-232.
[41]朴花子,郑善子,崔万善.汉黄芩素对脂多糖诱导细胞因子IL-6和趋化因子RANTES的影响[J].中药药理与临床,2008,(06):34-36.
[42] Venkatesh G, Ramanathan S, Nair NK, et al. Permeability of atenolol andpropranolol in the presence of dimethyl sulfoxide in rat single-pass intestinalperfusion assay with liquid chromatography/UV detection[J]. BiomedChromatogr,2007,21(5):484-90.
[43] Dackson K, Stone JA, Palin KJ, et al. Evaluation of the mass balanceassumption with respect to the two-resistance model of intestinal absorption byusing in situ single-pass intestinal perfusion of theophylline in rats[J]. J PharmSci,1992,81(4):321-5.
[44] Raoof AA, Butler J, Devane JG. Assessment of regional differences in intestinalfluid movement in the rat using a modified in situ single pass perfusion model[J].Pharm Res,1998,15(8):1314-6.
[45] Crowe A, Lemaire M. In vitro and in situ absorption of SDZ-RAD using ahuman intestinal cell line (Caco-2) and a single pass perfusion model in rats:comparison with rapamycin[J]. Pharm Res,1998,15(11):1666-72.
[46] Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenolred, and14C-PEG-3350methods to determine water absorption in the ratsingle-pass intestinal perfusion model[J]. AAPS PharmSci,2001,3(3):E25.
[47] Sutton SC, Rinaldi MT, McCarthy JM, et al. A statistical method for thedetermination of absorption rate constant estimated using the rat single passintestinal perfusion model and multiple linear regression[J]. J Pharm Sci,2002,91(4):1046-53.
[48] McLeod BJ, Zhang H, Huang L, et al. An in situ single-pass perfusion model forassessing absorption across the intestinal mucosa of the brushtail possum[J]. N ZVet J,2005,53(4):234-41.
[49] Boerner P, Evans-Laying M, U HS, et al. Polarity of neutral amino acid transportand characterization of a broad specificity transport activity in a kidneyepithelial cell line, MDCK[J]. J Biol Chem,1986,261(30):13957-62.
[50] Veronesi B. Characterization of the MDCK cell line for screeningneurotoxicants[J]. Neurotoxicology,1996,17(2):433-43.
[51] Karyekar CS, Eddington ND, Garimella TS, et al. Evaluation ofP-glycoprotein-mediated renal drug interactions in an MDR1-MDCK model[J].Pharmacotherapy,2003,23(4):436-42.
[52] Yang B, Lv Y, Chen Y, et al. Inhibitory action of soybean beta-conglycininhydrolysates on Salmonella typhimurium translocation in Caco-2epithelial cellmonolayers[J]. J Agric Food Chem,2008,56(16):7522-7.
[53] Zegura B, Volcic M, Lah TT, et al. Different sensitivities of human colonadenocarcinoma (CaCo-2), astrocytoma (IPDDC-A2) and lymphoblastoid(NCNC) cell lines to microcystin-LR induced reactive oxygen species and DNAdamage[J]. Toxicon,2008,52(3):518-25.
[54] Siissalo S, Zhang H, Stilgenbauer E, et al. The expression of mostUDP-glucuronosyltransferases (UGTs) is increased significantly during Caco-2cell differentiation, whereas UGT1A6is highly expressed also inundifferentiated cells[J]. Drug Metab Dispos,2008,36(11):2331-6.
[55] Mahler GJ, Shuler ML, Glahn RP. Characterization of Caco-2and HT29-MTXcocultures in an in vitro digestion/cell culture model used to predict ironbioavailability[J]. J Nutr Biochem,2009,20(7):494-502.
[56] Dai JY, Yang JL, Li C. Transport and metabolism of flavonoids from Chineseherbal remedy Xiaochaihu-tang across human intestinal Caco-2cellmonolayers[J]. Acta Pharmacol Sin,2008,29(9):1086-93.
[57] Yamada T, Saito N, Anraku M, et al. Physicochemical characterization of a newcrystal form and improvements in the pharmaceutical properties of the poorlywater-soluble antiosteoporosis drug3,9-bis(N,N-dimethylcarbamoy-loxy)-5H-benzofuro[3,2-c]quinoline-6-one(KCA-098) by solid dispersion with hydroxypropylcellulose[J]. Pharm DevTechnol,2000,5(4):443-54.
[58] Li YP, Zhang XY, Zhou JJ, et al. Preparation and dissolution property ofipriflavone solid dispersion[J]. Zhongguo Yao Li Xue Bao,1999,20(10):957-60.
[59] Xiao HB, Krucker M, Albert K, et al. Determination and identification ofisoflavonoids in Radix astragali by matrix solid-phase dispersion extraction andhigh-performance liquid chromatography with photodiode array and massspectrometric detection[J]. J Chromatogr A,2004,1032(1-2):117-24.
[60] Manhita AC, Teixeira DM, da CCT. Application of sample disruption methods inthe extraction of anthocyanins from solid or semi-solid vegetable samples[J]. JChromatogr A,2006,1129(1):14-20.
[61] Kwon SH, Kim SY, Ha KW, et al. Pharmaceutical evaluation of genistein-loadedpluronic micelles for oral delivery[J]. Arch Pharm Res,2007,30(9):1138-43.
[62] Sun N, Zhang X, Lu Y, et al. In vitro evaluation and pharmacokinetics in dogs ofsolid dispersion pellets containing Silybum marianum extract prepared byfluid-bed coating[J]. Planta Med,2008,74(2):126-32.
[63]杜玥,杨汉煜.液相色谱串联质谱法测定大鼠血浆中的汉黄芩素[J].药学学报,2002,(05):362-366.
[64]崔福德.药剂学（第5版）[M].人民卫生出版社,2007:1.
[65] Wrighton SA, Stevens JC. The human hepatic cytochromes P450involved indrug metabolism[J]. Crit Rev Toxicol,1992,22(1):1-21.
[66] Role of Drug Metabolism and Pharmacokinetics in Toxicologic Pathology.Proceedings of the13th International Symposium of the Society of ToxicologicPathologists. Charleston, South Carolina, June5-9,1994[J]. Toxicol Pathol,1995,23(2):97-234.
[67] Alavijeh MS, Palmer AM. The pivotal role of drug metabolism andpharmacokinetics in the discovery and development of new medicines[J].IDrugs,2004,7(8):755-63.
[68] Hsieh Y, Cheng KC, Wang Y, et al. The role of exploratory drug metabolism andpharmacokinetics in new drug research: case study-selection of a thrombinreceptor antagonist for development[J]. Curr Pharm Des,2009,15(19):2262-9.
[69] Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring inassociation with terfenadine use[J]. JAMA,1990,264(21):2788-90.
[70] Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoproteinand cytochrome P4503A coordinately up-regulate these proteins in human coloncarcinoma cells[J]. Mol Pharmacol,1996,49(2):311-8.
[71] Lo A, Burckart GJ. P-glycoprotein and drug therapy in organ transplantation[J].J Clin Pharmacol,1999,39(10):995-1005.
[72] Konishi Y, Hagiwara K, Shimizu M. Transepithelial transport of fluorescein inCaco-2cell monolayers and use of such transport in in vitro evaluation ofphenolic acid availability[J]. Biosci Biotechnol Biochem,2002,66(11):2449-57.
[73] Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir: effects on P-glycoproteintransport and CYP3A metabolism in vitro[J]. Drug Metab Dispos,2005,33(6):764-70.
[74] Luo FR, Paranjpe PV, Guo A, et al. Intestinal transport of irinotecan in Caco-2cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, andMRP1[J]. Drug Metab Dispos,2002,30(7):763-70.
[75] Tep J, Videmann B, Mazallon M, et al. Transepithelial transport of fusariotoxinnivalenol: mediation of secretion by ABC transporters[J]. Toxicol Lett,2007,170(3):248-58.
[76] Jia JX, Wasan KM. Effects of monoglycerides on rhodamine123accumulation,estradiol17beta-D-glucuronide bidirectional transport and MRP2proteinexpression within Caco-2cells[J]. J Pharm Pharm Sci,2008,11(3):45-62.
[77] Fujimoto H, Higuchi M, Watanabe H, et al. P-glycoprotein mediates effluxtransport of darunavir in human intestinal Caco-2and ABCB1gene-transfectedrenal LLC-PK1cell lines[J]. Biol Pharm Bull,2009,32(9):1588-93.
[78] Yee S. In vitro permeability across Caco-2cells (colonic) can predict in vivo(small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997,14(6):763-6.
[79] Krishna G, Chen K, Lin C, et al. Permeability of lipophilic compounds in drugdiscovery using in-vitro human absorption model, Caco-2[J]. Int J Pharm,2001,222(1):77-89.
[80] Fagerholm U. Prediction of human pharmacokinetics--gastrointestinalabsorption[J]. J Pharm Pharmacol,2007,59(7):905-16.
[81] Ruckert P, Bates SR, Fisher AB. Role of clathrin-and actin-dependentendocytotic pathways in lung phospholipid uptake[J]. Am J Physiol Lung CellMol Physiol,2003,284(6):L981-9.
[82]谢海棠,赵小辰. Caco-2细胞对人参皂苷Rg3的摄取及代谢研究[J].中国临床药理学与治疗学,2004,(03):257-260.
[83] Brunet JL, Maresca M, Fantini J, et al. Human intestinal absorption ofimidacloprid with Caco-2cells as enterocyte model[J]. Toxicol Appl Pharmacol,2004,194(1):1-9.
[84] Artursson P, Palm K, Luthman K. Caco-2monolayers in experimental andtheoretical predictions of drug transport[J]. Adv Drug Deliv Rev,2001,46(1-3):27-43.
[85] Yamashita S, Furubayashi T, Kataoka M, et al. Optimized conditions forprediction of intestinal drug permeability using Caco-2cells[J]. Eur J Pharm Sci,2000,10(3):195-204.
[86]杨秀伟,杨晓达,王莹,等.中药化学成分肠吸收研究中Caco-2细胞模型和标准操作规程的建立[J].中西医结合学报,2007,(06):634-641.
[87]张志宏,聂淑芳,王启明,等.双嘧达莫大鼠在体胃、肠吸收动力学研究[J].中国药学杂志,2009,(16):1229-1233.
[88]关颖,杨涛,崔福德,等.运用单向灌流模型研究抗糖尿病创新药物西格列松大鼠在体肠的吸收[J].沈阳药科大学学报,2006,(08):483-487.
[89] You J, Li QP, Yu YW, et al.[Absorption of zedoary oil in rat intestine using insitu single pass perfusion model][J]. Yao Xue Xue Bao,2004,39(10):849-53.
[90] Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenolred, and14C-PEG-3350methods to determine water absorption in the ratsingle-pass intestinal perfusion model[J]. AAPS PharmSci,2001,3(3):E25.
[91]胡一桥，钱陈钦，郑梁元，郁伟海，谭仁祥. Intestinal absorption of cefiximein rats[J]. Acta Pharmacologica Sinica,1999,(01):54-57.
[92]朱玲玲,李娟,王广基.地西泮的大鼠在体肠吸收机理研究[J].中国药科大学学报,2006,(06):507-511.
[93] Artursson P, Magnusson C. Epithelial transport of drugs in cell culture. II: Effectof extracellular calcium concentration on the paracellular transport of drugs ofdifferent lipophilicities across monolayers of intestinal epithelial (Caco-2)cells[J]. J Pharm Sci,1990,79(7):595-600.
[94] Fagerholm U, Johansson M, Lennernas H. Comparison between permeabilitycoefficients in rat and human jejunum[J]. Pharm Res,1996,13(9):1336-42.
[95] US Food and Drug Administration, Guidance for Industry, Bioanalytical MethodValidation, Centre for Drug Evaluation and Research (CDER), Rockville,2001[J].
[96] Chen X, Wang H, Du Y, et al. Quantitation of the flavonoid wogonin and itsmajor metabolite wogonin-7beta-D-glucuronide in rat plasma by liquidchromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt TechnolBiomed Life Sci,2002,775(2):169-78.
[97] Tsai TH, Chou CJ, Tsai TR, et al. Determination of wogonin in rat plasma byliquid chromatography and its pharmacokinetic application[J]. Planta Med,1996,62(3):263-6.
[98]许颖,柯学,平其能. HPLC法测定大鼠静脉注射汉黄芩素的血药浓度及其药动学研究[J].药学与临床研究,2007,(01):35-38.
[99] Zuo F, Zhou ZM, Zhang Q, et al. Pharmacokinetic study on themulti-constituents of Huangqin-Tang decoction in rats[J]. Biol Pharm Bull,2003,26(7):911-9.
[100] Du Y, Chen XY, Yang HY, et al.[Determination of wogonin in rat plasma byliquid chromatography-tandem mass spectrometry][J]. Yao Xue Xue Bao,2002,37(5):362-6.
[101] Tsai TH, Chou CJ, Tsai TR, et al. Determination of wogonin in rat plasma byliquid chromatography and its pharmacokinetic application[J]. Planta Med,1996,62(3):263-6.
[102] Peng J, Qi Q, You Q, et al. Subchronic toxicity and plasma pharmacokineticstudies on wogonin, a natural flavonoid, in Beagle dogs[J]. J Ethnopharmacol,2009,124(2):257-62.
[103] Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of itsmetabolism, pharmacokinetics and drug interactions[J]. Clin Pharmacokinet,2005,44(5):467-94.
[104] Kuntzman R, Levin W, Jacobson M, et al. Studies on microsomal hydroxylationand the demonstration of a new carbon monoxide binding pigment in livermicrosomes[J]. Life Sci II,1968,7(4):215-24.
[105] Morris DL, Davila JC. Analysis of rat cytochrome P450isoenzyme expressionusing semi-quantitative reverse transcriptase-polymerase chain reaction(RT-PCR)[J]. Biochem Pharmacol,1996,52(5):781-92.
[106] Schott B, Bennis S, Pourquier P, et al. Differential over-expression of mdr1genes in multidrug-resistant rat glioblastoma cell lines selected with doxorubicinor vincristine[J]. Int J Cancer,1993,55(1):115-21.
[107] Quinn AM, Penning TM. Comparisons of(+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol activation by human cytochromeP450and aldo-keto reductase enzymes: effect of redox state and expressionlevels[J]. Chem Res Toxicol,2008,21(5):1086-94.
[108] Koop DR. Oxidative and reductive metabolism by cytochrome P4502E1[J].FASEB J,1992,6(2):724-30.
[1]陈翠丽,徐广飞,顾海鹰,纪康,蒲明亮.黄芩中汉黄芩素的提取研究.交通医学.2008.(02):128-129.
[2]喻春皓,张萍,王宏志.纤维素酶辅助提取生黄芩饮片中黄酮苷元的工艺研究.安徽农业科学.2009.(35):17692-17694+17697.
[3]高中洪,卞曙光.黄芩黄酮对自由基引起的大鼠脑线粒体损伤的保护作用.中国药理学通报.2000.(01):81-83.
[4]高中洪,徐辉碧.黄芩黄酮对自由基的清除作用的ESR研究.华中理工大学学报.1999.(01):98-100.
[5] Sato T, Kawamoto A, Tamura A, Tatsumi Y, Fujii T. Mechanism of antioxidantaction of pueraria glycoside (PG)-1(an isoflavonoid) and mangiferin (axanthonoid). Chem Pharm Bull (Tokyo).1992.40(3):721-4.
[6]高中洪,徐辉碧.黄芩黄酮对H_2O_2导致的神经细胞损伤的保护作用.中国药理学通报.2000.(05):589-590.
[7] Chung CP, Park JB, Bae KH. Pharmacological effects of methanolic extractfrom the root of Scutellaria baicalensis and its flavonoids on human gingivalfibroblast. Planta Med.1995.61(2):150-3.
[8] Lin CC, Shieh DE. The anti-inflammatory activity of Scutellaria rivularisextracts and its active components, baicalin, baicalein and wogonin. Am J ChinMed.1996.24(1):31-6.
[9] Kim HK, Cheon BS, Kim YH, Kim SY, Kim HP. Effects of naturally occurringflavonoids on nitric oxide production in the macrophage cell line RAW264.7and their structure-activity relationships. Biochem Pharmacol.1999.58(5):759-65.
[10] Huang WH, Lee AR, Yang CH. Antioxidative and anti-inflammatory activities ofpolyhydroxyflavonoids of Scutellaria baicalensis GEORGI. Biosci BiotechnolBiochem.2006.70(10):2371-80.
[11] Lim BO, Choue RW, Lee HY, Seong NS, Kim JD. Effect of the flavonoidcomponents obtained from Scutellaria radix on the histamine, immunoglobulinE and lipid peroxidation of spleen lymphocytes of Sprague-Dawley rats. BiosciBiotechnol Biochem.2003.67(5):1126-9.
[12] Chang YL, Shen JJ, Wung BS, Cheng JJ, Wang DL. Chinese herbal remedywogonin inhibits monocyte chemotactic protein-1gene expression in humanendothelial cells. Mol Pharmacol.2001.60(3):507-13.
[13] Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E(2)production in macrophages. Eur J Pharmacol.2000.406(3):477-81.
[14] Jang S, Bak EJ, Kim M, et al. Wogonin inhibits osteoclast formation induced bylipopolysaccharide. Phytother Res.2009.
[15] Nakamura N, Hayasaka S, Zhang XY, et al. Effects of baicalin, baicalein, andwogonin on interleukin-6and interleukin-8expression, and nuclearfactor-kappab binding activities induced by interleukin-1beta in human retinalpigment epithelial cell line. Exp Eye Res.2003.77(2):195-202.
[16] Heo HJ, Lee HJ, Kim YS, et al. Effects of baicalin and wogonin on mucinrelease from cultured airway epithelial cells. Phytother Res.2007.21(12):1130-4.
[17] Enomoto R, Suzuki C, Koshiba C, et al. Wogonin prevents immunosuppressiveaction but not anti-inflammatory effect induced by glucocorticoid. Ann N YAcad Sci.2007.1095:412-7.
[18] Pal M, Joshi H, Kapoor VP, Pushpangadan P, Chaurasia L. Antifungal activity ofwogonin. Phytother Res.2003.17(10):1215-6.
[19] Chaudhuri PK, Srivastava R, Kumar S, Kumar S. Phytotoxic and antimicrobialconstituents of Bacopa monnieri and Holmskioldia sanguinea. Phytother Res.2004.18(2):114-7.
[20]胡道道，房喻，马宁，孙作民，曹治权.汉黄芩素与铜（Ⅱ）、钴（Ⅱ）、镍（Ⅱ）固体配合物的合成、表征及抑菌活性研究.陕西师大学报(自然科学版).1994.(01):31-34.
[21] Ma SC, Du J, But PP, et al. Antiviral Chinese medicinal herbs against respiratorysyncytial virus. J Ethnopharmacol.2002.79(2):205-11.
[22] Huang RL, Chen CC, Huang HL, et al. Anti-hepatitis B virus effects of wogoninisolated from Scutellaria baicalensis. Planta Med.2000.66(8):694-8.
[23] Guo Q, Zhao L, You Q, et al. Anti-hepatitis B virus activity of wogonin in vitroand in vivo. Antiviral Res.2007.74(1):16-24.
[24]林红,胡格,索占伟,伊鹏霏,胡屹屹,穆祥.中药有效成分诱导肺微血管内皮细胞表达IFN-γ的研究.北京农学院学报.2008.(03):46-49.
[25] Sonoda M, Nishiyama T, Matsukawa Y, Moriyasu M. Cytotoxic activities offlavonoids from two Scutellaria plants in Chinese medicine. J Ethnopharmacol.2004.91(1):65-8.
[26]王旭光,方琦.汉黄芩素对HL-60细胞端粒酶活性的影响.四川医学.2004.(08):854-855.
[27] Zhang HW, Yang Y, Zhang K, et al. Wogonin induced differentiation and G1phase arrest of human U-937leukemia cells via PKCdelta phosphorylation. EurJ Pharmacol.2008.591(1-3):7-12.
[28] Zhang K, Guo QL, You QD, et al. Wogonin induces the granulocyticdifferentiation of human NB4promyelocytic leukemia cells and up-regulatesphospholipid scramblase1gene expression. Cancer Sci.2008.99(4):689-95.
[29] Nou-Ying Tang CS, Chung GCaJ. Wogonin inhibits WEHI-3leukemia cells inBlab/C mice In Vivo. The FASEB Journal.2007.21:728-15.
[30] Himeji M, Ohtsuki T, Fukazawa H, et al. Difference of growth-inhibitory effectof Scutellaria baicalensis-producing flavonoid wogonin among human cancercells and normal diploid cell. Cancer Lett.2007.245(1-2):269-74.
[31]陈新美,贾强.汉黄芩素体外抗骨肉瘤作用的研究.中国药房.2009.(36):2813-2814.
[32] Wang W, Guo QL, You QD, et al. The Anticancer Activities of Wogonin inMurine Sarcoma S180both in Vitro and in Vivo. Biol Pharm Bull.2006.29(6):1132-7.
[33]黎丹戎,张玮.汉黄芩素诱导人卵巢癌细胞A2780凋亡及对细胞端粒酶活性的影响.癌症.2003.(08):801-805.
[34]张汉英,黎丹戎,李力,张玮.汉黄芩素对移植人卵巢癌SKOV3细胞裸鼠组织端粒酶蛋白hTERT影响与凋亡相关性研究.时珍国医国药.2008.(08):1987-1989.
[35] Lu N, Gao Y, Ling Y, et al. Wogonin suppresses tumor growth in vivo andVEGF-induced angiogenesis through inhibiting tyrosine phosphorylation ofVEGFR2. Life Sci.2008.82(17-18):956-63.
[36] Wang W, Guo Q, You Q, et al. Involvement of bax/bcl-2in wogonin-inducedapoptosis of human hepatoma cell line SMMC-7721. Anticancer Drugs.2006.17(7):797-805.
[37] Ikemoto S, Sugimura K, Yoshida N, et al. Antitumor effects of Scutellariae radixand its components baicalein, baicalin, and wogonin on bladder cancer cell lines.Urology.2000.55(6):951-5.
[38] Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson PS.Characterization of chemical constituents in Scutellaria baicalensis withantiandrogenic and growth-inhibitory activities toward prostate carcinoma. ClinCancer Res.2005.11(10):3905-14.
[39] Cho J, Lee HK. Wogonin inhibits ischemic brain injury in a rat model ofpermanent middle cerebral artery occlusion. Biol Pharm Bull.2004.27(10):1561-4.
[40] Lee H, Kim YO, Kim H, et al. Flavonoid wogonin from medicinal herb isneuroprotective by inhibiting inflammatory activation of microglia. FASEB J.2003.17(13):1943-4.
[41] Piao HZ, Choi IY, Park JS, et al. Wogonin inhibits microglial cell migration viasuppression of nuclear factor-kappa B activity. Int Immunopharmacol.2008.8(12):1658-62.
[42]朴花子,于兆霞,朴日龙,李迎军.汉黄芩素对脂多糖诱导一氧化氮和单核细胞趋化蛋白-1的影响.中药药理与临床.2007.(03):20-21.
[43]朴花子,崔弘,朴日龙,李迎军.汉黄芩素对脂多糖诱导的促炎性因子的影响.西安交通大学学报(医学版).2008.(02):230-232.
[44]朴花子,郑善子,崔万善.汉黄芩素对脂多糖诱导细胞因子IL-6和趋化因子RANTES的影响.中药药理与临床.2008.(06):34-36.
[45] Park HG, Yoon SY, Choi JY, et al. Anticonvulsant effect of wogonin isolatedfrom Scutellaria baicalensis. Eur J Pharmacol.2007.574(2-3):112-9.
[46] Hui KM, Huen MS, Wang HY, et al. Anxiolytic effect of wogonin, abenzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi.Biochem Pharmacol.2002.64(9):1415-24.
[47] Kong EK, Huang Y, Sanderson JE, Chan KB, Yu S, Yu CM. Baicalein andWogonin inhibit collagen deposition in SHR and WKY cardiac fibroblastcultures. BMB Rep.2010.43(4):297-303.
[48] Lin CM, Chang H, Chen YH, Li SY, Wu IH, Chiu JH. Protective role ofwogonin against lipopolysaccharide-induced angiogenesis via VEGFR-2, notVEGFR-1. Int Immunopharmacol.2006.6(11):1690-8.
[49]王立明，张如松，方瑞英，葛文再.黄芩有效成分对四氯化碳致伤的原代培养大鼠肝细胞的作用.浙江医科大学学报.1996.(06):241-244.
[50] Qi Q, Peng J, Liu W, et al. Toxicological studies of wogonin in experimentalanimals. Phytother Res.2009.23(3):417-22.
[51] Peng J, Qi Q, You Q, et al. Subchronic toxicity and plasma pharmacokineticstudies on wogonin, a natural flavonoid, in Beagle dogs. J Ethnopharmacol.2009.124(2):257-62.
[52]许颖,柯学,平其能. HPLC法测定大鼠静脉注射汉黄芩素的血药浓度及其药动学研究.药学与临床研究.2007.(01):35-38.
[53]杜玥,杨汉煜.液相色谱串联质谱法测定大鼠血浆中的汉黄芩素.药学学报.2002.(05):362-366.
[54] Chen X, Wang H, Du Y, Zhong D. Quantitation of the flavonoid wogonin and itsmajor metabolite wogonin-7beta-D-glucuronide in rat plasma by liquidchromatography-tandem mass spectrometry. J Chromatogr B Analyt TechnolBiomed Life Sci.2002.775(2):169-78.
[55]柯学,许颖,严菲,平其能.汉黄芩素脂质体的制备及大鼠体内药代动力学.中国药科大学学报.2007.(06):502-506.
[56]徐倩,邓丹丹,曹志娟,谢琼,梁建英,卢建忠.荧光法和分子对接研究4种黄酮与血清白蛋白的相互作用.分析化学.2010.(04):483-487.
[57] Tian J, Liu J, Xie J, Yao X, Hu Z, Chen X. Binding of wogonin to human serumalbumin: a common binding site of wogonin in subdomain IIA. J PhotochemPhotobiol B.2004.74(1):39-45.
[58] Liu Y, He W, Gao W, Hu Z, Chen X. Binding of wogonin to humangammaglobulin. Int J Biol Macromol.2005.37(1-2):1-11.
[59] Lin YT, Hsiu SL, Hou YC, Chen HY, Chao PD. Degradation of flavonoidaglycones by rabbit, rat and human fecal flora. Biol Pharm Bull.2003.26(5):747-51.
[60] Kim BR, Kim DH, Park R, et al. Effect of an extract of the root of Scutellariabaicalensis and its flavonoids on aflatoxin B1oxidizing cytochrome P450enzymes. Planta Med.2001.67(5):396-9.
[61] Si D, Wang Y, Zhou YH, et al. Mechanism of CYP2C9inhibition by flavonesand flavonols. Drug Metab Dispos.2009.37(3):629-34.