银杏叶提取物自乳化给药体系的制备及银杏叶提取物—药物相互作用的研究
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摘要
银杏叶提取物(Ginkgo biloba extracts，GBE)是国内外常用的中药，临床上广泛用于提高老年人的认知作用等疾病。GBE的主要活性成分是5-7％的萜内酯(银杏内酯和白果内酯)和22-27％的黄酮醇糖苷(如：苷元槲皮素、山奈素和异鼠李素)。在不同品牌的银杏叶固体制剂中，由于GBE主要活性组分的溶解度差，溶出度和生物利用度存在差异大、重现性差等问题。自乳化药物传递系统(SEDDS)是由油、表面活性剂和助表面活性剂组成的均一混合物，当它进入胃肠道遇到水相介质可在轻微搅拌和胃肠的蠕动下自发乳化形成乳剂。研究表明SEDDS的快速自发乳化和在吸收部位的高度分散能有效的提高水难溶性药物的口服吸收。GBE作为心脑血管疾病治疗与预防的常用药物，一般需长期用药，在临床上与其它药物合用的几率较大。因此，本文从这两方面入手，旨在研究制备GBE自乳化给药系统以提高主要成分的吸收，并对GBE与其他药物相互作用进行研究，为临床合理用药和预防不良反应提供理论依据。
处方前研究表明，25℃时GBE在丙二醇和甘油两种助表面活性剂中的溶解度较其他辅料大；建立了GBE主要成分含量测定和溶出度测定的分析方法，采用先将黄酮苷水解为苷元，再用HPLC-UV法测定银杏黄酮苷的含量和溶出度；分别采用HPLC-ELSD法和HPLC-ESI-MS法测定银杏萜内酯的含量和溶出度。
选用油酸乙酯和Miglyol 812为油相，丙二醇为助表面活性剂，Tween 80、T_(50)C_(50)(50％Tween 80-50％Cremophor EL35)为乳化剂，通过绘制假三元相图，确定自乳化区域大小。油酸乙酯为油相所形成的自乳化区域显著大于Miglyol 812，混合表面活性剂T_(50)C_(50)与Tween 80相比自乳化区域稍有增加。考察了温度、搅拌强度、介质的pH和稀释倍数等外在因素对自乳化效率的影响，最终选择37℃、低速搅拌、蒸馏水稀释500倍作为稀释介质来评价SEDDS的自乳化效率。GBE的加入对自乳化区域无影响，但使自乳化时间延长，所形成乳剂的粒径增大。最终用于溶出度和生物利用度研究的处方为GBE-油酸乙酯-T_(50)C_(50)-丙二醇(12.5：45：45：10)。所制备的GBE自乳化胶囊20min时，各主要成分的溶出度可达90％以上，而对照片剂20min时，各主要成分的溶出度不足40％。加速和室温留样试验结果表明，GBE自乳化系统稳定性良好。
建立了灵敏、专属的HPLC-ESI-MS方法测定家犬血浆中银杏内酯和白果内酯的浓度，该方法的最低定量限：银杏内酯B为2.5 ng／ml，白果内酯、银杏内酯A和C为10 ng／ml，该方法的日内日间精密度和准确度均＜15％。对GBE自乳化胶囊和普通片剂进行了家犬体内药物动力学研究，结果表明与片剂相比，给予自乳化胶囊后白果内酯、银杏内酯A和B的T_(max)均明显缩短，C_(max)显著增加，分别增加了44.8％、52.4％和44.4％(p＜0.05)，AUC_(0-10h)也显著增加。给予GBE自乳化胶囊和普通片剂后，白果内酯、银杏内酯A和银杏内酯B的相对生物利用度分别为162.1±42.5％、154.6±65.3％和155.8±26.8％。对AUC_(0-t)和C_(max)分别进行方差分析，并进一步采用双单侧检验和(1-2α)置信区间法分析，结果表明GBE SEDDS胶囊和片剂相比，白果内酯、银杏内酯A和B的吸收程度生物不等效。
茶碱为咖啡因类生物碱之一、具有较强的松弛支气管平滑肌，兴奋心脏及利尿作用，也有一定的中枢兴奋作用，且治疗窗很窄(5～20μg／ml)。本文考察了大鼠连续5天口服GBE后对茶碱体内药动学的影响，大鼠静脉给予茶碱(10 mg／kg)，经GBE 10 mg／kg和100 mg／kg前处理组与对照组相比，茶碱清除率分别为对照组的1.3倍和1.7倍：口服给予茶碱(10 mg/kg)，茶碱清除率分别为对照组的1.5倍和1.7倍(p＜0.05)，经GBE 100mg／kg前处理，茶碱注射给药和口服给药后AUC_(0-24h)分别下降了40％和38％。表明GBE前处理可能增加了大鼠CYP1A2的活性，从而增加了茶碱的清除率。
采用外翻肠囊法，以非索非那定和噻利洛尔(这两个药物均为P-gp的典型底物)为模型药物，考察GBE及其主要成分是否对P-gp底物的转运产生影响。盐酸维拉帕米(P-gp的典型抑制剂)可显著增加非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量约2倍(p＜0.01)，槲皮素可显著增加非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量(p＜0.05)，这一结果与文献报道槲皮素是P-gp抑制剂的结论相一致。但GBE、芦丁和银杏内酯对非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量无显著影响。
Ginkgo biloba extracts (GBE) have become a widely used herbal remedy for increasing cognitive function in elderly people in the USA, Europe, Japan and many other countries. The primary active components of GBE include 5-7% terpene lactones (ginkgolides and bilobalide) and 22-27% ginkgo flavonol glycosides (e.g., the flavones quercetin, kaempferol, and isorhamnetin). The dissolution and bioavailability of the primary active components from the oral solid preparations of different Ginkgo biloba brands were obviously different and irreproducible, due to the lower solubility of the active components. Self-emulsifying drug delivery systems (SEDDS) are homogeneous mixtures of oils, surfactants and cosolvent, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. It was found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. GBE needs long-term administering medicine to the patients, especially to elderly patients, for treatment and prevention cerebrovascular diseases. The interactions of GBE and other drugs may occur in all probability in the clinic. So the main purpose of the present study is to prepare SEDDS for improving oral absorption of GBE and to investigate the interactions of GBE and drugs. The results will provide theory bases for clinical administration and prevention of side effects.In the pre-formulation study, the solubility of GBE in 1,2-propanediol and glycerol was higher than other chose vehicles at 25℃. The methods of content and dissolution determination for the active components of GBE were developed and validated. The flavonol glycosides were determined after hydrolyzing by HPLC-UV for content and dissolution. The terpene lactones were determined by HPLC-ELSD and HPLC-ESI-MS for the contents and dissolutions, respectively.
Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsifying region using Miglyol 812 and ethyl oleate as oils, 1, 2-propanediol as cosolvent, Tween 80 and T_(50)C_(50)(50％Tween 80-50％Cremophor EL35) as emulsifiers. For both systems, the self-enulsifying region was larger when ethyl oleate as oil than Miglyol 812. The mixed surfactant T_(50)C_(50) increased the self-emulsifying region slightly comparing with Tween 80 at the same weight level. We investigated the effects of temperature, flow shape, pH and volume of media on the self-emulsifying efficiency. At last, the conditions of 37℃, low speed and diluting with 500-fold volume of the distilled water were used for evaluating the efficiency of self-emulsifying. GBE did not affect the self-emulsifying region, but prolonged self-emulsifying time and increased the droplet size comparing with the blank vehicles. Optimum formulation for in vitro dissolution and bioavailability assessment consisted of 45％T_(50)C_(50), 45％ethyl oleate and 10％1, 2-propanediol. The content of GBE was fixed at 12.5％w/w of the vehicle. The in vitro dissolution rates of the active components of GBE from optimum SEDDS were faster than those of the GBE tablets. The dissolution of SEDDS at 20 rain was more than 90％, and the dissolution of tablet at 20 rain was less than 40％. The stability of GBE SEDDS was good in the accelerated test and under room temperature.
A sensitive and selective method using HPLC-ESI-MS was developed for the quantification of bilobalide and ginkgolides in canine plasma. The lower limit of quantification (LLOQ) of the method was 2.5 ng/ml for ginkgolide B and 10.0 ng/ml for bilabolide, ginkgolide A and ginkgolide C. The accuracy of the method was within 15％of the actual values over a wide range of plasma concentrations. The intra-day and inter-day precision was better than 15％(R.S.D.). The plasma profiles of ginkgolides and bilobalide in dogs following oral administration of tablets and self-emulsifying formulation of GBE at a single dose of 800 mg (3BE were investigated. The short T_(max) values of SEDDS for all three tested components showed the fairly rapid onset compared to the conventional tablets. The marked differences were also observed for the C_(max). The C_(max) of SEDDS increased 44.8％, 52.4％and 44.4％for bilobalide gikgolide A and B compared to the conventional tablets, respectively. And the AUC_(0-10h) of SEDDS was increased significantly comparing with the conventional tablets. The relative bioavailability of bilobalide, ginkgolide A and ginkgolide B was 162.1±42.5％, 154.6±65.3％and 155.8±26.8％, respectively. These data clearly demonstrate the utility of SEDDS in improving the rate and extent of oral absorption of GBE. The analysis variance, two-one sided tests and (1-2α) confidence interval analysis of main pharmacokinetic parameters showed that the absorptions of bilobalide, ginkgolide A and B for SEDDS and tablets were not bioequivalence.
This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window (5～20μg/ml) used for the treatment of asthma. GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30 percent (GBE 10 mg/kg, p＜0.05) and 70 percent (GBE 100 mg/kg, p＜0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After pretreatment with GBE (100 mg/kg), the AUC_(0-24h) of theophylline was reduced by 40％following intravenous administration and by 38％following oral administration. These results demonstrated that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.
The aim of this study is to investigate the effects of GBE and the active components of GBE on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. The efflux of P-gp substrates from rat everted sac in the absence or presence Of verapamil, GBE, rutin, quercetin or terpene lactones was measured. Fexofenadine and celiprolol were used as P-gp substrates. Verapamil and the quercetin inhibited the efflux from the intestine of the two drugs tested. GBE, rutin and terpene lactones did not affect the efflux of fexofenadine and celiprolol in the intestine.
处方前研究表明，25℃时GBE在丙二醇和甘油两种助表面活性剂中的溶解度较其他辅料大；建立了GBE主要成分含量测定和溶出度测定的分析方法，采用先将黄酮苷水解为苷元，再用HPLC-UV法测定银杏黄酮苷的含量和溶出度；分别采用HPLC-ELSD法和HPLC-ESI-MS法测定银杏萜内酯的含量和溶出度。
选用油酸乙酯和Miglyol 812为油相，丙二醇为助表面活性剂，Tween 80、T_(50)C_(50)(50％Tween 80-50％Cremophor EL35)为乳化剂，通过绘制假三元相图，确定自乳化区域大小。油酸乙酯为油相所形成的自乳化区域显著大于Miglyol 812，混合表面活性剂T_(50)C_(50)与Tween 80相比自乳化区域稍有增加。考察了温度、搅拌强度、介质的pH和稀释倍数等外在因素对自乳化效率的影响，最终选择37℃、低速搅拌、蒸馏水稀释500倍作为稀释介质来评价SEDDS的自乳化效率。GBE的加入对自乳化区域无影响，但使自乳化时间延长，所形成乳剂的粒径增大。最终用于溶出度和生物利用度研究的处方为GBE-油酸乙酯-T_(50)C_(50)-丙二醇(12.5：45：45：10)。所制备的GBE自乳化胶囊20min时，各主要成分的溶出度可达90％以上，而对照片剂20min时，各主要成分的溶出度不足40％。加速和室温留样试验结果表明，GBE自乳化系统稳定性良好。
建立了灵敏、专属的HPLC-ESI-MS方法测定家犬血浆中银杏内酯和白果内酯的浓度，该方法的最低定量限：银杏内酯B为2.5 ng／ml，白果内酯、银杏内酯A和C为10 ng／ml，该方法的日内日间精密度和准确度均＜15％。对GBE自乳化胶囊和普通片剂进行了家犬体内药物动力学研究，结果表明与片剂相比，给予自乳化胶囊后白果内酯、银杏内酯A和B的T_(max)均明显缩短，C_(max)显著增加，分别增加了44.8％、52.4％和44.4％(p＜0.05)，AUC_(0-10h)也显著增加。给予GBE自乳化胶囊和普通片剂后，白果内酯、银杏内酯A和银杏内酯B的相对生物利用度分别为162.1±42.5％、154.6±65.3％和155.8±26.8％。对AUC_(0-t)和C_(max)分别进行方差分析，并进一步采用双单侧检验和(1-2α)置信区间法分析，结果表明GBE SEDDS胶囊和片剂相比，白果内酯、银杏内酯A和B的吸收程度生物不等效。
茶碱为咖啡因类生物碱之一、具有较强的松弛支气管平滑肌，兴奋心脏及利尿作用，也有一定的中枢兴奋作用，且治疗窗很窄(5～20μg／ml)。本文考察了大鼠连续5天口服GBE后对茶碱体内药动学的影响，大鼠静脉给予茶碱(10 mg／kg)，经GBE 10 mg／kg和100 mg／kg前处理组与对照组相比，茶碱清除率分别为对照组的1.3倍和1.7倍：口服给予茶碱(10 mg/kg)，茶碱清除率分别为对照组的1.5倍和1.7倍(p＜0.05)，经GBE 100mg／kg前处理，茶碱注射给药和口服给药后AUC_(0-24h)分别下降了40％和38％。表明GBE前处理可能增加了大鼠CYP1A2的活性，从而增加了茶碱的清除率。
采用外翻肠囊法，以非索非那定和噻利洛尔(这两个药物均为P-gp的典型底物)为模型药物，考察GBE及其主要成分是否对P-gp底物的转运产生影响。盐酸维拉帕米(P-gp的典型抑制剂)可显著增加非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量约2倍(p＜0.01)，槲皮素可显著增加非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量(p＜0.05)，这一结果与文献报道槲皮素是P-gp抑制剂的结论相一致。但GBE、芦丁和银杏内酯对非索非那定和噻利洛尔从粘膜侧至浆膜侧的转运量无显著影响。
Ginkgo biloba extracts (GBE) have become a widely used herbal remedy for increasing cognitive function in elderly people in the USA, Europe, Japan and many other countries. The primary active components of GBE include 5-7% terpene lactones (ginkgolides and bilobalide) and 22-27% ginkgo flavonol glycosides (e.g., the flavones quercetin, kaempferol, and isorhamnetin). The dissolution and bioavailability of the primary active components from the oral solid preparations of different Ginkgo biloba brands were obviously different and irreproducible, due to the lower solubility of the active components. Self-emulsifying drug delivery systems (SEDDS) are homogeneous mixtures of oils, surfactants and cosolvent, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. It was found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. GBE needs long-term administering medicine to the patients, especially to elderly patients, for treatment and prevention cerebrovascular diseases. The interactions of GBE and other drugs may occur in all probability in the clinic. So the main purpose of the present study is to prepare SEDDS for improving oral absorption of GBE and to investigate the interactions of GBE and drugs. The results will provide theory bases for clinical administration and prevention of side effects.In the pre-formulation study, the solubility of GBE in 1,2-propanediol and glycerol was higher than other chose vehicles at 25℃. The methods of content and dissolution determination for the active components of GBE were developed and validated. The flavonol glycosides were determined after hydrolyzing by HPLC-UV for content and dissolution. The terpene lactones were determined by HPLC-ELSD and HPLC-ESI-MS for the contents and dissolutions, respectively.
Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsifying region using Miglyol 812 and ethyl oleate as oils, 1, 2-propanediol as cosolvent, Tween 80 and T_(50)C_(50)(50％Tween 80-50％Cremophor EL35) as emulsifiers. For both systems, the self-enulsifying region was larger when ethyl oleate as oil than Miglyol 812. The mixed surfactant T_(50)C_(50) increased the self-emulsifying region slightly comparing with Tween 80 at the same weight level. We investigated the effects of temperature, flow shape, pH and volume of media on the self-emulsifying efficiency. At last, the conditions of 37℃, low speed and diluting with 500-fold volume of the distilled water were used for evaluating the efficiency of self-emulsifying. GBE did not affect the self-emulsifying region, but prolonged self-emulsifying time and increased the droplet size comparing with the blank vehicles. Optimum formulation for in vitro dissolution and bioavailability assessment consisted of 45％T_(50)C_(50), 45％ethyl oleate and 10％1, 2-propanediol. The content of GBE was fixed at 12.5％w/w of the vehicle. The in vitro dissolution rates of the active components of GBE from optimum SEDDS were faster than those of the GBE tablets. The dissolution of SEDDS at 20 rain was more than 90％, and the dissolution of tablet at 20 rain was less than 40％. The stability of GBE SEDDS was good in the accelerated test and under room temperature.
A sensitive and selective method using HPLC-ESI-MS was developed for the quantification of bilobalide and ginkgolides in canine plasma. The lower limit of quantification (LLOQ) of the method was 2.5 ng/ml for ginkgolide B and 10.0 ng/ml for bilabolide, ginkgolide A and ginkgolide C. The accuracy of the method was within 15％of the actual values over a wide range of plasma concentrations. The intra-day and inter-day precision was better than 15％(R.S.D.). The plasma profiles of ginkgolides and bilobalide in dogs following oral administration of tablets and self-emulsifying formulation of GBE at a single dose of 800 mg (3BE were investigated. The short T_(max) values of SEDDS for all three tested components showed the fairly rapid onset compared to the conventional tablets. The marked differences were also observed for the C_(max). The C_(max) of SEDDS increased 44.8％, 52.4％and 44.4％for bilobalide gikgolide A and B compared to the conventional tablets, respectively. And the AUC_(0-10h) of SEDDS was increased significantly comparing with the conventional tablets. The relative bioavailability of bilobalide, ginkgolide A and ginkgolide B was 162.1±42.5％, 154.6±65.3％and 155.8±26.8％, respectively. These data clearly demonstrate the utility of SEDDS in improving the rate and extent of oral absorption of GBE. The analysis variance, two-one sided tests and (1-2α) confidence interval analysis of main pharmacokinetic parameters showed that the absorptions of bilobalide, ginkgolide A and B for SEDDS and tablets were not bioequivalence.
This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window (5～20μg/ml) used for the treatment of asthma. GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30 percent (GBE 10 mg/kg, p＜0.05) and 70 percent (GBE 100 mg/kg, p＜0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After pretreatment with GBE (100 mg/kg), the AUC_(0-24h) of theophylline was reduced by 40％following intravenous administration and by 38％following oral administration. These results demonstrated that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.
The aim of this study is to investigate the effects of GBE and the active components of GBE on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. The efflux of P-gp substrates from rat everted sac in the absence or presence Of verapamil, GBE, rutin, quercetin or terpene lactones was measured. Fexofenadine and celiprolol were used as P-gp substrates. Verapamil and the quercetin inhibited the efflux from the intestine of the two drugs tested. GBE, rutin and terpene lactones did not affect the efflux of fexofenadine and celiprolol in the intestine.
引文
[1] 康辉，黄矛．银杏叶提取物药理学研究概况．药学实践杂志．2002，20(6)：334-8．
[2] 钱天秀，杨世林，徐丽珍等．银杏研究现状．国外医药—植物分册．1997，12(4)：157-63．
[3] 祝国光．银杏叶制剂的欧共体标准及启示—“2000年欧共体天然植物药市场经济论坛”会议后几个问题答复(一)．中国中医药信息杂志．2001，8(1)：84-85，87．
[4] 植松大辅．银杏叶提取物．日本医学介绍．2005，26(3)：133-5．
[5] 李新岗，薛荣．银杏叶制剂的心脑血管药理及其临床应用．国外医学—脑血管疾病分册．1995，3(6)：310-3．
[6] Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997, 29(1-2): 413-580.
[7] 杨秀芬，王乃平，曾繁典．中药有效成分对药物代谢酶的影响．中国中药杂志．2002，27(5)： 325-8．
[8] Yang XF, Wang NP, Lu WH, Zeng FD. Effects of Ginkgo biloba extract and tanshinone on cytochrome P-450 isozymes and glutathione transferase in rats. Acta Pharmacol Sin. 2003, 24(10): 1033-8.
[9] Umegaki K, Saito K, Kubota Y, Sanada H, Yarnada K, Shinozuka K. Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats. Jpn J Pharmacol. 2002, 90(4): 345-51.
[10] Shinozuka K, Umegaki K, Kubota Y, Tanaka N, Mizuno H, Yarnauchi J, Nakamura K, Kunitomo M. Feeding of Ginkgo biloba extract (GBE) enhances gene expression of hepatic eytechrome P-450 and attenuates the hypotensive effect of nicardipine in rats. Life Sci. 2002, 70(23): 2783-92.
[11] Sugiyama T, Kubota Y, Shinozuka K, Yamada S, Wu J, Umegaki K. Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytoehrome P450 mediated mechanism in aged rats. Life Sci. 2004, 75(9): 1113-22.
[12] Kubota Y, Kobayashi K, Tanaka N, Nakamura K, Kunitomo M, Umegaki K, Shinozuka K. Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats. J Pharm Pharmacol. 2004, 56(3): 401-5.
[13] Ohnishi N, Kusuhara M, Yoshioka M, Kuroda K, Soga A, Nishikawa F, Koishi T, Nakagawa M, Hori S, Matsumoto T, Yamashita M, Ohta S, Takara K, Yokoyama T. Studies on interactions between ftmetional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokineties of diltiazem in rats. Biol Pharm Bull. 2003, 26(9): 1315-20.
[14] Gaudineau C, Beckerman R, Welbourn S, Auclair K. Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract. Biochem Biophys Res Commun. 2004, 318(4): 1072-8.
[15] yon Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harrnatz JS, Goldman P, Greenblatt DJ. Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol. 2004, 56(8): 1039-44.
[16] Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 2002, 71(13): 1579-89.
[17] Kuo I, Chen J, Chang TK. Effect of Ginkgo biloba extract on rat hepatic microsomal CYP1A activity: role of ginkgolides, bilobalide, and flavonols. Can J Physiol Pharmacol. 2004, 82(1): 57-64.
[18] Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002, 72(3): 276-87.
[19] Fromm MF. The influence of MDRI polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev. 2002, 54(10): 1295-310.
[20] Morris ME, Zhang S. Flavonoid-drug interactions: Effects of flavonoids on ABC transporters. Life Sci. 2006, 78(18): 2116-30.
[21] Gottesman MM, Pastan Ⅰ. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993, 62: 385-427.
[22] Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdrla P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995, 96(4): 1698-705
[23] Tsuruo T, Iida H, Kitatani Y, Yokota K, Tsukagoshi S, Sekurai Y. Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincistine and adriamycin in drug-resistant tumor cells. Cancer Res. 1984, 44(10): 4303-7.
[24] Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT, Ambudkar SV, Pastan I, Dey S. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry. 1998, 37(11): 3594-601.
[25] Meador J, Sweet P, Stupecky M, Wetzel M, Murray S, Gupta S, Slater L. Enhancement by cyclosporin A of daunorubicin efficacy in Ehrlich ascites carcinoma and mutine hepatoma 129. Cancer Res. 1987, 47(23): 6216-9.
[26] Horio M, Chin KV, Currier SJ, Goldenberg S, Williams C, Pastan I, Gottesman MM, Handler J. Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia. J Biol Chem. 1989, 264(25): 14880-4.
[27] Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R. Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem. 1992, 267(34): 24248-52.
[28] van Kalken CK, Broxterman HJ, Pinedo HM, Feller N, Dekker H, Lankelma J, Giaccoue G. Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br J Cancer. 1993, 67(2): 284-9.
[29] Knsuhara H, Suzuki H, Sugiyama Y. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J Pharm Sci. 1998, 87(9): 1025-40.
[30] de Graaf D, Shanna RC, Mechetner EB, Schimke RT, Roninson IB. P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc Natl Acad Sci USA. 1996, 93(3): 1238-42.
[31] Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV, Roninson IB. Involvement of MDR1 P-glycoprotein in multifactorial resistance to mothotrexate. Int J Cancer. 1996, 65(5):613-9.
[32] Potschka H, Loscher W. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain harrier of rats. Epilepsia. 2001, 42(10): 1231-40.
[33] Dupuy J, Larrieu G, Sutra JF, Lespine A, Alvinerie M. Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Vet Parasitol. 2003, 112(4): 337-47.
[34] Choi JS, Choi HK, Shin SC. Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats. Int J Pharm. 2004, 275(1-2): 165-70.
[35] Choi JS, Jo BW, Kim YC. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur J Pharm Biopharm. 2004, 57(2): 313-8.
[36] Wang YH, Chao PD, Hsin SL, Wen KC, Hou YC. Lethal quercetin-digoxin interaction in pigs. Life Sci. 2004, 74(10): 1191-7.
[37] Shah NH, Carvajal MT, Patel CI, et al. Self-emulsifying drug delivery systems(SEDDS)with polyglycolzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm. 1994, 106(1): 15-23.
[38] Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res. 1995, 12(11): 1561-72.
[39] Robinson JR. Introduction: Semi-solid formulations for oral drug delivery. BT Gttefosse. 1996, 89: 11-13.
[40] Palin KJ, Phillips AJ, Ning A. The oral absorption of cefoxitin from oil and emulsion vehicles in rats. Int J Pharm. 1986, 33: 99-104.
[41] Myers RA, Stella VJ. Systemic bioavailability of penclomedine(NSC-338720)from oil-in-water emulsions administered intraduodenally to rats. Int J Pharm. 1992, 78:217-226.
[42] Kararli TT, Needham TE, Griffin M, Schoenhard G, Ferro LJ, Alcorn L. Oral delivery of a renin inhibitor compound using emulsion formulations. Pharm Res. 1992, 9(7): 888-93.
[43] 陆彬．药物新型与新技术．北京：人民卫生出版社．1998．53．
[44] Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Del Rev. 1997, 25(4): 47-58.
[45] Kovarik JM, Mueller EA, van Bree JB, Tetzloff W, Kutz K. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci. 1994, 83(3): 444-6.
[46] Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavallability assessment. Int J Pharm. 2001, 212(2): 233-46.
[47] Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm. 2000, 50 (1): 179-88.
[48] Wei L, Sun P, Nie S, Pan W. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm. 2005, 31(8): 785-94.
[49] 沈海蓉，李中东，钟明康．阿托伐他汀自微乳释药系统的制备和评价．药学学报．2005，40(11)： 982-7．
[50] You J, Cui FD, Li QP, Hart X, Yu YW, Yang MS. A novel formulation design about water-insoluble oily druy. preparation of zedoary turmeric oil microspheres with self-emulsifying ability and evaluation in rabbits. Int J Pharm. 2005, 288(2): 315-23.
[51] Cui SM, Zhao CS, Chen DW, He ZG Self-microemulsifying drug delivery systems(SMEDDS) for improving in vitro dissolution and oral absorption of pueraria lobata isoflavone. Drug Dev Ind Pharm. 2005, 31(4-5): 349-56.
[52] Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the efficiency of a self-emulsifying oral delivery system. Drug Dev Ind Pharm. 1997, 23(8): 809-12.
[53] Solomon J, Harry Seager, Pouton CW. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Delivery Rev. 1997, (25): 33-46.
[54] Craig DQM, Lievens HSR Pitt KG Storey DE. An investigation into physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int J Pharm. 1993, 96: 147-55.
[55] 张正全，陆彬．微乳给药系统研究概况．中国医药工业杂志．2001，32(3)：139-42．
[56] 王晓黎，蒋雪涛．微乳在药剂学上的应用．解发军药学学报．2000，18(2)：88-91．
[57] 平其能等．现代药剂学．北京：中国医药科技出版社．1998，1-9．
[58] 李开泉，陈武．银杏叶化学成分研究进展．宜春医专学报．2000，12(4)：335-7．
[59] Hasler A, Sticher O, Meier O. Identification and detemination of the flavonoids from Ginkgo biloba by high performance liquid chromatography. J Chromatogr. 1992, 605: 41-8.
[60] 刘桂霞，孙玉玮，金兆祥．银杏叶的研究进展．国外药—植物药分册．1994，9(1)：10-4．
[61] Hasler A, Gross GA, Meier B, Sticher O. Complex flavonol glycosides from the leaves of Ginkgo biloba. Phytochemistry. 1992, 31(4): 1391-4.
[62] 刘仲则．中草药黄酮类化合物心血管活性成份概述．中草药．1987，18：34-42．
[63] Liu Y, Liu Y, Dai Y, Xun L, Hu M. Enteric disposition and recycling of flavonoids and ginkgo flavonoids. J Altern Complement Med. 2003, 9(5): 631-40.
[64] 王成章，沈兆邦，陈祥．银杏叶聚戊烯醇化学研究．林产化学工业．1992，12(4)：279-86．
[65] Defeudis FV. Ginkgo biloba extract (EGb761): pharmacological activities and clinical applications. Paris: Elsevier. 1991, 9-94.
[66] 葛月宾．银杏叶提取物速释滴丸的设计与评价．沈阳药科大学硕士学位论文．31-2．
[67] van Beek TA. Ginkgolides and bilobalide: their physical, chromatographic and spectroscopic properties. Bioorg Med Chem. 2005, 13(17): 5001-12.
[68] 庄向平，虞杏英，杨更生．银杏叶中黄酮含量的测定和提取方法．中草药．1992，23(3)：122-4．
[69] 刘重芳，吴志荣，方青汉．银杏叶总黄酮提取工艺探讨．中成药．1992，14(7)：8-9．
[70] 李梅，杨正鸿，王坚毅．紫外分光光度法测定复方银杏胶囊中银杏叶总黄酮含量．中国医院药学杂志．1998，18(2)：85-7．
[71] 李吉来，于留荣，曾宇珠．薄层扫描法测定银杏叶中总黄酮醇甙的含量．中国中药杂志．1996，21(2)：106-8．
[72] Pietta PG, Maur PL, Rave A. Application of micelle electrokinetics capillary chromatography to the determination of flavonoid drugs. J Chromatography, 1991,549: 367-73.
[73] Marc P Maillard, Jean-Lucwolfender, Kurt Hostettmann. Use of liquid chromatographythermospray mass spectrometry in phytochemical analysis of crude plant extracts. J Chromatography. 1993, 647: 147-54.
[74] 姚渭溪．银杏叶中活性成分的提取工艺、测定及其进展．中草药．1995，26(3)：157-9．
[75] 杨义芳．银杏叶及其制剂的定性定量分析．国外医药-植物分册．1995，10(4)：14-6．
[76] 田南卉，王秸，历进忠．高效液相色谱法蒸发激光散射检测器测定银杏叶提取物中内酯的含量．药物分析杂志．1997，17(4)：28-9．
[77] Chauret N, Carrier J, Mancini M. Gas chromatography-mass spectrometric analysis of ginkgolides produced by Ginkgo biloba cell culture. J Chromatography. 1991,588:281-7.
[78] 颜玉贞，谢培山，钱浩良．银杏叶提取物及制剂萜类内酯薄层色谱荧光扫描定量测定研究．中国中药杂志．1997，22(3)：159-62．
[79] 陈仲良．银杏叶提取物的化学成分和制剂的质量．中国中药杂志．1996，31(6)：326-31．
[80] Steinke B, Muller B, Wagner H. Biological standardization of Ginkgo extracts. Planta Med. 1993, 59(2): 155-60.
[81] 中国药典2000年版增补本．一部．银杏叶片．8-9．
[82] Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004, 58(3): 173-82.
[83] Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992, 9: 87-93.
[84] Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different Ginkgo biloba brands. J Pharm Pharmacol. 2002, 54(5): 661-9.
[85] Kressmann S, Biber A, Wonnemann M, Schug B, Blume HH, Muller WE. Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations. J Pharm Pharmacol. 2002, 54(11): 1507-14.
[86] Swenson ES, Milisen WB, Curatolo W. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm Res. 1994, 11(8): 1132-42.
[87] Li P, Ghosh A, Wagner RF, Krill S, Joshi YM, Serajuddin AT. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. Int J Pharm. 2005, 288(1): 27-34.
[88] Craig DQM, Barker SA, Banning D, et al. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm. 1995, 114(1): 103-10.
[89] Khoo SM, Humberstone, A J, Porter CJH, et al. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm. 1998, 167: 155-64.
[90] Halbant L, Barbe c, Pozo A D. An investigation into physical and chemical properties of semi-solid self-emulsifying systems for hard gelatin capsules, lnt J Pharm. 1996, 130: 203-12.
[91] Pouton CW. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int J Pharm. 1985, 27: 335-48.
[92] 徐贵霞，王玉丽，全东琴．自乳化释药系统的体外评价．解放军药学学报．2003，19(3)：195-7．
[93] Kim JY, Ku YS. Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats. Int J Pharm. 2000, 194(I): 81-9.
[94] Walgren RA, Lin JT, Kiune RK, Walle T. Cellular uptake of dietary flavonoid quercetin 4'-beta-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol Exp Ther. 2000, 294(3): 837-43.
[95] Walgren RA, Kamaky KJ Jr, Lindenmayer GE, Walle T. Efflux of dietary flavonoid quercetin 4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J Pharmacol Exp Ther. 2000, 294(3): 830-6.
[96] Li CL, Wong YY. The bioavailability of ginkgolides in Ginkgo biloba extracts. Planta Med. 1997, 63(6): 563-5.
[97] Biber A, Koch E. Bioavailability of ginkgolides and bilobalide from extracts of ginkgo biloba using GC/MS. Planta Med. 1999, 65(2): 192-3.
[98] Mauri P, Simonetti P, Gardana C, Minoggio M, Morazzoni P, Bombardelli E, Pietta P. Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry of terpene lactones in plasma of volunteers dosed with Ginkgo biloba L. extracts. Rapid Commun Mass Spectrom. 2001, 15(12): 929-34.
[99] Mauri P, Minoggio M, Iemoli L, Rossoni G; Morazzoni P, Bombardelli E, Pietta P. Liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry of terpene lactones in plasma of animals. J Pharm Biomed Anal. 2003, 32(4-5): 633-9.
[100] Lo YL. Relationships between the hydrophilie-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. J Control Release. 2003, 90(1): 37-48.
[101] Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992, 22(1): 1-21.
[102] Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 1994, 26(2): 144-60.
[103] Dogra SC, Whitelaw ML, May BK. Transcriptional activation of cytochrome P450 genes by different classes of chemical inducers. Clin Exp Pharmacol Physiol. 1998, 25(1): 1-9.
[104] 胡云珍，姚彤炜．细胞色素P450 1A的研究进展．中国药学杂志．2003，38：246-50．
[105] 许振华，周宏灏．细胞色素氧化酶P450 1A2与药物代谢．中国临床药理学杂志．1996，12：115-21．
[106] 陈刚．治疗药物监测．北京：人民军医出版社．1988，358．
[107] Ohnishi A., Kato M., Kojima J., Ushiama H., Yoneko M., Kawai H. Differential pharmacokinetics of theophylline in elderly patients. Drugs..Aging. 2003, 20(1): 71-84.
[108] Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet. 1978, 3(4): 267-93.
[109] Grygiel JJ, Miners JO, Drew R, Birkett DJ. Differential effects of cimetidine on theophylline metabolic pathways. Eur J Clin Pharmacol. 1984, 26(3): 335-40.
[110] Campbell ME, Grant DM, Inaba T, Kalow W. Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos. 1987, 15(2): 237-49.
[111] Rogge MC, Solomon WR, Sedman AJ, Welling PC, Toothaker RD, Wagner JG. The theophylline-enoxacin interaction: Ⅰ. Effect of enoxacin dose size on theophylline disposition. Clin Pharmacol 7her. 1988, 44(5): 579-87.
[112] Gu L, Gonzalez FJ, Kalow W, Tang BK. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYPlA2 and CYP2E1. Pharmacogenetics. 1992, 2(2): 73-7.
[113] Sarkat MA, Hunt C, Guzelian PS, Karnes HT. Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos. 1992, 20(1): 31-7.
[114] Teunissen MW, Brorens IO, Geerlings JM, Breimer DD. Dose-dependent elimination of theophylline in rats.Xenobiotica. 1985, 15(2): 165-71.
[115] Crygiel JJ, Wing LM, Farkas J, Birkett DJ. Effects of allopurinol on theophylline metabolism and clearance. Clin Pharmacol Ther. 1979, 26(5): 660-7.
[116] Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S. Effect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers. J Clin Pharmacol. 2004, 44(1): 95-101.
[117] Barnes PJ. Therapy of chronic obstructive pulmonary disease. Pharmacol Ther. 2003, 97(1): 87-94.
[118] Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995, Suppl 1: 20-5.
[119] Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implicatios. Am Fam Physician. 1998, 57(1): 107-16.
[120] Smith TJ, Guo Z, Guengerich FP, Yang CS. Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)by human cytochrome P450 1A2 and its inhibition by phenethyl isothiocyanate. Carcinogenesis. 1996, 17(4): 809-13.
[121] Bachmann K, Sanyal G, Potter J, Schiavone R, Loch J. In vivo evidence that theophylline is metabolized principally by CYP1A in rats. Pharmacology. 1993, 47(1): 1-7.
[122] Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992, 340(8828): 1136-9.
[123] Canivenc-Lavier MC, Vemevaut MF, Totis M, Siess MH, Magdalou J, Suschetet M. Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver. Toxicology. 1996, 114(1): 19-27.
[124] Siess MH, Mas JP, Canivenc-Lavier MC, Suschetet M. Time course of induction of rat hepatic drug-metabolizing enzyme activities following dietary administration of flavonoids. J Toxicol Environ Health. 1996, 49(5): 481-96.
[125] 杨秀芬，王乃平，曾繁典．银杏内酯对大鼠肝细胞色素P450基因表达的影响．中国中药杂志．2005，30：1009-13，
[126] Balimane PV, Patel K, Marino A, Chong S. Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery. Eur J Pharm Biopharm. 2004, 58(1): 99-105.
[127] Takara K, Tsujimoto M, Ohnishi N, Yokoyama T. Digoxin up-regulates MDR1 in human colon carcinoma Caco-2 cells. Biochem Biophys Res Commun. 2002, 292(1): 190-4.
[128] Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res. 2002, 19(6): 765-72.
[129] Choi CH, Kim JH, Kim SH. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR. Biochem Biophys Res Commun. 2004, 320(3): 672-9.
[130] Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001, 299(2): 620-8.
[131] Berggren S, Heogstraate J, Fagerholm U, Lennernas H. Characterization of jejunal absorption and apical efflux of ropivacalne, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models. Eur JPharm Sci. 2004, 21(4): 553-60.
[132] Doppenschmitt S, Spahn-Langguth H, Regardh CG, Langguth P. Radioligand-binding assay employing P-glycoprotein-overexpressing cells: testing drug affinities to the secretory intestinal multidrug transporter. Pharm Res. 1998, 15(7): 1001-6.
[133] Garrigues A, Nugier J, Orlowski S, Ezan E. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal Biochem. 2002, 305(1): 106-14.
[134] Schmid D, Ecker G, Kopp S, Hitzler M, Chiba P. Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol. 1999, 58(9): 1447-56.
[135] Meyer S, Noisommit-Rizzi N, Reuss M, Neubauer P. Optimized analysis of intracellular adenosine and guanosine phosphates in Escherichia coli. Anal Biochem. 1999, 271(1): 43-52.
[136] Pento JT, Mousissian GK. Time-dependent deterioration of active transport in duodenal segments of rat intestine. J Pharmacol Methods. 1988, 20(1): 9-14.
[137] Barthe L, Woodley JF, Kenworthy S, Houin G. An improved everted gut sac as a simple and accurate technique to measure paracellular transport across the small intestine. Eur J Drug Metab Pharmacokinet. 1998, 23(2): 313-23.
[138] Mauro VF, Mauro LS, Kleshinski JF, Khuder SA, Wang Y, Erhardt PW. Impact of ginkgo biloba on the pharmacokinetics of digoxin. Am J Ther. 2003, 10(4): 247-51.
[139] Perloff MD, von Moltke LL, Greenblatt DJ. Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol. 2002, 42(11): 1269-74.
[140] Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001, 69(3): 114-21.
[141] Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John's wort on the phatmacokinefics of fexofenadine. Clin Pharmacol Ther. 2002, 71(6): 414-20.
[142] Davit B, Reynolds K, Yuan R, Ajayi F, Conner D, Fadiran E, Gillespie B, Sahajwalla C, Huang SM, Lesko LJ. FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling. J Clin Pharmacol. 1999, 39(9): 899-910.
[143] Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther. 2001, 23(3): 451-66.
[144] Hartmann C, Krauss D, Spahn H, Mutschler E. Simultaneous determination of (R)- and (S)-celiprolol in human plasma and urine: high-performance liquid chromatographic assay on a chiral stationary phase with fluorimetric detection. J Chromatogr. 1989, 496(2): 387-96.
[145] Hitzenberger, G, Takaca, F., Pittner, H., 1983. Pharmakokinetik des P-Rezeptorenblockers Celiprolol nach einmaliger intraventiser und oraler Gabe. Arzneim: Forsch./Drug. Res. 33(1), 50-2.
[146] Lipka E, Spahn-Langguth H, Mutschler E, Amidon GL. In vivo non-linear intestinal permeability of celiprolol and propranolol in conscious dogs: evidence for intestinal secretion. Eur J Pharm Sci. 1998, 6(1): 75-81.
[147] Karlsson J, Kuo SM, Ziemniak J, Artursson P. Transport of celiprolol across human intestinal epithelial(Caco-2)cells: mediation of secretion by multiple transporters including P-glyeoprotein. Br J Pharmacol. 1993, 110(3): 1009-16.
[148] Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Honin G, Impact of excipients on the absorption of P-glyeoprotein substrates in vitro and in vivo. Int J Pharm. 2004, 278(1): 119-31.
[149] 平其能等．现化药剂学．北京．中国医药科技出版社．1998：177-87．
[150] Petal N, Tannergren C, Rungstad D, Lennemas H. Transport characteristics of fexofenadine in the Caco-2 cell model. Pharm Res. 2004, 21(8): 1398-404.
[151] Tian R, Koyabu N, Takanaga H, Matsuo H, Ohtani H, Sawada Y. Effects of grapefruit juice and orange juice on the intestinal effiux of P-glyeoprotein substrates. Pharm Res. 2002, 19(6): 802-9.
[152] Jonker C, Hamman JH, Kotze AF. Intestinal paracellular permeation enhancement with quatemised chitosan: in situ and in vitro evaluation. Int J Pharm. 2002, 238(1-2): 205-13.
[153] Tomei S, Torimoto M, Hayashi Y, Inoue K, Yuasa H, Watanabe J. Kinetic characterization of carrier-mediated transport systems for D-glucose and taurocholate in the everted sacs of the rat colon. Biol Pharm Bull. 2003, 26(6): 899-901.
[154] Kitagawa S, Nabekura T, Takahashi T, Nakamura Y, Sakamoto H, Tano H, Hirai M, Tsukahara G. Structure-activity relationships of the inhibitory effects of flavonoids on P-glyeoprotein-mediated transport in KB-C2 cells. Biol Pharm Bull. 2005, 28(12): 2274-8.
[155] Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. lnt J Pharm. 2006, 313(1-2): 144-9.
[156] Wang Y, Cao J, Zeng S. Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin. J Pharm Pharmacol. 2005, 57(6): 751-8.
[157] ofer M, Wolffram S, Koggel A, Spahn-Langguth H, Langguth P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur J Pharm Sci. 2005, 25(2-3): 263-71.
[158] Yang ZG, Meng H, Zhang X, Li XD, Lv WL, Zhang Q. Effect of quercetin on the aeyelovir intestinal absorption. Beijing Da Xue Xue Bao. 2004, 36(3): 309-12.
[2] 钱天秀，杨世林，徐丽珍等．银杏研究现状．国外医药—植物分册．1997，12(4)：157-63．
[3] 祝国光．银杏叶制剂的欧共体标准及启示—“2000年欧共体天然植物药市场经济论坛”会议后几个问题答复(一)．中国中医药信息杂志．2001，8(1)：84-85，87．
[4] 植松大辅．银杏叶提取物．日本医学介绍．2005，26(3)：133-5．
[5] 李新岗，薛荣．银杏叶制剂的心脑血管药理及其临床应用．国外医学—脑血管疾病分册．1995，3(6)：310-3．
[6] Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997, 29(1-2): 413-580.
[7] 杨秀芬，王乃平，曾繁典．中药有效成分对药物代谢酶的影响．中国中药杂志．2002，27(5)： 325-8．
[8] Yang XF, Wang NP, Lu WH, Zeng FD. Effects of Ginkgo biloba extract and tanshinone on cytochrome P-450 isozymes and glutathione transferase in rats. Acta Pharmacol Sin. 2003, 24(10): 1033-8.
[9] Umegaki K, Saito K, Kubota Y, Sanada H, Yarnada K, Shinozuka K. Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats. Jpn J Pharmacol. 2002, 90(4): 345-51.
[10] Shinozuka K, Umegaki K, Kubota Y, Tanaka N, Mizuno H, Yarnauchi J, Nakamura K, Kunitomo M. Feeding of Ginkgo biloba extract (GBE) enhances gene expression of hepatic eytechrome P-450 and attenuates the hypotensive effect of nicardipine in rats. Life Sci. 2002, 70(23): 2783-92.
[11] Sugiyama T, Kubota Y, Shinozuka K, Yamada S, Wu J, Umegaki K. Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytoehrome P450 mediated mechanism in aged rats. Life Sci. 2004, 75(9): 1113-22.
[12] Kubota Y, Kobayashi K, Tanaka N, Nakamura K, Kunitomo M, Umegaki K, Shinozuka K. Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats. J Pharm Pharmacol. 2004, 56(3): 401-5.
[13] Ohnishi N, Kusuhara M, Yoshioka M, Kuroda K, Soga A, Nishikawa F, Koishi T, Nakagawa M, Hori S, Matsumoto T, Yamashita M, Ohta S, Takara K, Yokoyama T. Studies on interactions between ftmetional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokineties of diltiazem in rats. Biol Pharm Bull. 2003, 26(9): 1315-20.
[14] Gaudineau C, Beckerman R, Welbourn S, Auclair K. Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract. Biochem Biophys Res Commun. 2004, 318(4): 1072-8.
[15] yon Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harrnatz JS, Goldman P, Greenblatt DJ. Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm Pharmacol. 2004, 56(8): 1039-44.
[16] Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 2002, 71(13): 1579-89.
[17] Kuo I, Chen J, Chang TK. Effect of Ginkgo biloba extract on rat hepatic microsomal CYP1A activity: role of ginkgolides, bilobalide, and flavonols. Can J Physiol Pharmacol. 2004, 82(1): 57-64.
[18] Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002, 72(3): 276-87.
[19] Fromm MF. The influence of MDRI polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev. 2002, 54(10): 1295-310.
[20] Morris ME, Zhang S. Flavonoid-drug interactions: Effects of flavonoids on ABC transporters. Life Sci. 2006, 78(18): 2116-30.
[21] Gottesman MM, Pastan Ⅰ. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993, 62: 385-427.
[22] Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdrla P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995, 96(4): 1698-705
[23] Tsuruo T, Iida H, Kitatani Y, Yokota K, Tsukagoshi S, Sekurai Y. Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincistine and adriamycin in drug-resistant tumor cells. Cancer Res. 1984, 44(10): 4303-7.
[24] Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT, Ambudkar SV, Pastan I, Dey S. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry. 1998, 37(11): 3594-601.
[25] Meador J, Sweet P, Stupecky M, Wetzel M, Murray S, Gupta S, Slater L. Enhancement by cyclosporin A of daunorubicin efficacy in Ehrlich ascites carcinoma and mutine hepatoma 129. Cancer Res. 1987, 47(23): 6216-9.
[26] Horio M, Chin KV, Currier SJ, Goldenberg S, Williams C, Pastan I, Gottesman MM, Handler J. Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia. J Biol Chem. 1989, 264(25): 14880-4.
[27] Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R. Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem. 1992, 267(34): 24248-52.
[28] van Kalken CK, Broxterman HJ, Pinedo HM, Feller N, Dekker H, Lankelma J, Giaccoue G. Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br J Cancer. 1993, 67(2): 284-9.
[29] Knsuhara H, Suzuki H, Sugiyama Y. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J Pharm Sci. 1998, 87(9): 1025-40.
[30] de Graaf D, Shanna RC, Mechetner EB, Schimke RT, Roninson IB. P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc Natl Acad Sci USA. 1996, 93(3): 1238-42.
[31] Norris MD, De Graaf D, Haber M, Kavallaris M, Madafiglio J, Gilbert J, Kwan E, Stewart BW, Mechetner EB, Gudkov AV, Roninson IB. Involvement of MDR1 P-glycoprotein in multifactorial resistance to mothotrexate. Int J Cancer. 1996, 65(5):613-9.
[32] Potschka H, Loscher W. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain harrier of rats. Epilepsia. 2001, 42(10): 1231-40.
[33] Dupuy J, Larrieu G, Sutra JF, Lespine A, Alvinerie M. Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Vet Parasitol. 2003, 112(4): 337-47.
[34] Choi JS, Choi HK, Shin SC. Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats. Int J Pharm. 2004, 275(1-2): 165-70.
[35] Choi JS, Jo BW, Kim YC. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur J Pharm Biopharm. 2004, 57(2): 313-8.
[36] Wang YH, Chao PD, Hsin SL, Wen KC, Hou YC. Lethal quercetin-digoxin interaction in pigs. Life Sci. 2004, 74(10): 1191-7.
[37] Shah NH, Carvajal MT, Patel CI, et al. Self-emulsifying drug delivery systems(SEDDS)with polyglycolzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J Pharm. 1994, 106(1): 15-23.
[38] Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption; physical and biopharmaceutical aspects. Pharm Res. 1995, 12(11): 1561-72.
[39] Robinson JR. Introduction: Semi-solid formulations for oral drug delivery. BT Gttefosse. 1996, 89: 11-13.
[40] Palin KJ, Phillips AJ, Ning A. The oral absorption of cefoxitin from oil and emulsion vehicles in rats. Int J Pharm. 1986, 33: 99-104.
[41] Myers RA, Stella VJ. Systemic bioavailability of penclomedine(NSC-338720)from oil-in-water emulsions administered intraduodenally to rats. Int J Pharm. 1992, 78:217-226.
[42] Kararli TT, Needham TE, Griffin M, Schoenhard G, Ferro LJ, Alcorn L. Oral delivery of a renin inhibitor compound using emulsion formulations. Pharm Res. 1992, 9(7): 888-93.
[43] 陆彬．药物新型与新技术．北京：人民卫生出版社．1998．53．
[44] Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Del Rev. 1997, 25(4): 47-58.
[45] Kovarik JM, Mueller EA, van Bree JB, Tetzloff W, Kutz K. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci. 1994, 83(3): 444-6.
[46] Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavallability assessment. Int J Pharm. 2001, 212(2): 233-46.
[47] Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm. 2000, 50 (1): 179-88.
[48] Wei L, Sun P, Nie S, Pan W. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm. 2005, 31(8): 785-94.
[49] 沈海蓉，李中东，钟明康．阿托伐他汀自微乳释药系统的制备和评价．药学学报．2005，40(11)： 982-7．
[50] You J, Cui FD, Li QP, Hart X, Yu YW, Yang MS. A novel formulation design about water-insoluble oily druy. preparation of zedoary turmeric oil microspheres with self-emulsifying ability and evaluation in rabbits. Int J Pharm. 2005, 288(2): 315-23.
[51] Cui SM, Zhao CS, Chen DW, He ZG Self-microemulsifying drug delivery systems(SMEDDS) for improving in vitro dissolution and oral absorption of pueraria lobata isoflavone. Drug Dev Ind Pharm. 2005, 31(4-5): 349-56.
[52] Bachynsky MO, Shah NH, Patel CI, et al. Factors affecting the efficiency of a self-emulsifying oral delivery system. Drug Dev Ind Pharm. 1997, 23(8): 809-12.
[53] Solomon J, Harry Seager, Pouton CW. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Delivery Rev. 1997, (25): 33-46.
[54] Craig DQM, Lievens HSR Pitt KG Storey DE. An investigation into physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis. Int J Pharm. 1993, 96: 147-55.
[55] 张正全，陆彬．微乳给药系统研究概况．中国医药工业杂志．2001，32(3)：139-42．
[56] 王晓黎，蒋雪涛．微乳在药剂学上的应用．解发军药学学报．2000，18(2)：88-91．
[57] 平其能等．现代药剂学．北京：中国医药科技出版社．1998，1-9．
[58] 李开泉，陈武．银杏叶化学成分研究进展．宜春医专学报．2000，12(4)：335-7．
[59] Hasler A, Sticher O, Meier O. Identification and detemination of the flavonoids from Ginkgo biloba by high performance liquid chromatography. J Chromatogr. 1992, 605: 41-8.
[60] 刘桂霞，孙玉玮，金兆祥．银杏叶的研究进展．国外药—植物药分册．1994，9(1)：10-4．
[61] Hasler A, Gross GA, Meier B, Sticher O. Complex flavonol glycosides from the leaves of Ginkgo biloba. Phytochemistry. 1992, 31(4): 1391-4.
[62] 刘仲则．中草药黄酮类化合物心血管活性成份概述．中草药．1987，18：34-42．
[63] Liu Y, Liu Y, Dai Y, Xun L, Hu M. Enteric disposition and recycling of flavonoids and ginkgo flavonoids. J Altern Complement Med. 2003, 9(5): 631-40.
[64] 王成章，沈兆邦，陈祥．银杏叶聚戊烯醇化学研究．林产化学工业．1992，12(4)：279-86．
[65] Defeudis FV. Ginkgo biloba extract (EGb761): pharmacological activities and clinical applications. Paris: Elsevier. 1991, 9-94.
[66] 葛月宾．银杏叶提取物速释滴丸的设计与评价．沈阳药科大学硕士学位论文．31-2．
[67] van Beek TA. Ginkgolides and bilobalide: their physical, chromatographic and spectroscopic properties. Bioorg Med Chem. 2005, 13(17): 5001-12.
[68] 庄向平，虞杏英，杨更生．银杏叶中黄酮含量的测定和提取方法．中草药．1992，23(3)：122-4．
[69] 刘重芳，吴志荣，方青汉．银杏叶总黄酮提取工艺探讨．中成药．1992，14(7)：8-9．
[70] 李梅，杨正鸿，王坚毅．紫外分光光度法测定复方银杏胶囊中银杏叶总黄酮含量．中国医院药学杂志．1998，18(2)：85-7．
[71] 李吉来，于留荣，曾宇珠．薄层扫描法测定银杏叶中总黄酮醇甙的含量．中国中药杂志．1996，21(2)：106-8．
[72] Pietta PG, Maur PL, Rave A. Application of micelle electrokinetics capillary chromatography to the determination of flavonoid drugs. J Chromatography, 1991,549: 367-73.
[73] Marc P Maillard, Jean-Lucwolfender, Kurt Hostettmann. Use of liquid chromatographythermospray mass spectrometry in phytochemical analysis of crude plant extracts. J Chromatography. 1993, 647: 147-54.
[74] 姚渭溪．银杏叶中活性成分的提取工艺、测定及其进展．中草药．1995，26(3)：157-9．
[75] 杨义芳．银杏叶及其制剂的定性定量分析．国外医药-植物分册．1995，10(4)：14-6．
[76] 田南卉，王秸，历进忠．高效液相色谱法蒸发激光散射检测器测定银杏叶提取物中内酯的含量．药物分析杂志．1997，17(4)：28-9．
[77] Chauret N, Carrier J, Mancini M. Gas chromatography-mass spectrometric analysis of ginkgolides produced by Ginkgo biloba cell culture. J Chromatography. 1991,588:281-7.
[78] 颜玉贞，谢培山，钱浩良．银杏叶提取物及制剂萜类内酯薄层色谱荧光扫描定量测定研究．中国中药杂志．1997，22(3)：159-62．
[79] 陈仲良．银杏叶提取物的化学成分和制剂的质量．中国中药杂志．1996，31(6)：326-31．
[80] Steinke B, Muller B, Wagner H. Biological standardization of Ginkgo extracts. Planta Med. 1993, 59(2): 155-60.
[81] 中国药典2000年版增补本．一部．银杏叶片．8-9．
[82] Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004, 58(3): 173-82.
[83] Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res. 1992, 9: 87-93.
[84] Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different Ginkgo biloba brands. J Pharm Pharmacol. 2002, 54(5): 661-9.
[85] Kressmann S, Biber A, Wonnemann M, Schug B, Blume HH, Muller WE. Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations. J Pharm Pharmacol. 2002, 54(11): 1507-14.
[86] Swenson ES, Milisen WB, Curatolo W. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm Res. 1994, 11(8): 1132-42.
[87] Li P, Ghosh A, Wagner RF, Krill S, Joshi YM, Serajuddin AT. Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. Int J Pharm. 2005, 288(1): 27-34.
[88] Craig DQM, Barker SA, Banning D, et al. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm. 1995, 114(1): 103-10.
[89] Khoo SM, Humberstone, A J, Porter CJH, et al. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm. 1998, 167: 155-64.
[90] Halbant L, Barbe c, Pozo A D. An investigation into physical and chemical properties of semi-solid self-emulsifying systems for hard gelatin capsules, lnt J Pharm. 1996, 130: 203-12.
[91] Pouton CW. Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification. Int J Pharm. 1985, 27: 335-48.
[92] 徐贵霞，王玉丽，全东琴．自乳化释药系统的体外评价．解放军药学学报．2003，19(3)：195-7．
[93] Kim JY, Ku YS. Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats. Int J Pharm. 2000, 194(I): 81-9.
[94] Walgren RA, Lin JT, Kiune RK, Walle T. Cellular uptake of dietary flavonoid quercetin 4'-beta-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol Exp Ther. 2000, 294(3): 837-43.
[95] Walgren RA, Kamaky KJ Jr, Lindenmayer GE, Walle T. Efflux of dietary flavonoid quercetin 4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J Pharmacol Exp Ther. 2000, 294(3): 830-6.
[96] Li CL, Wong YY. The bioavailability of ginkgolides in Ginkgo biloba extracts. Planta Med. 1997, 63(6): 563-5.
[97] Biber A, Koch E. Bioavailability of ginkgolides and bilobalide from extracts of ginkgo biloba using GC/MS. Planta Med. 1999, 65(2): 192-3.
[98] Mauri P, Simonetti P, Gardana C, Minoggio M, Morazzoni P, Bombardelli E, Pietta P. Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry of terpene lactones in plasma of volunteers dosed with Ginkgo biloba L. extracts. Rapid Commun Mass Spectrom. 2001, 15(12): 929-34.
[99] Mauri P, Minoggio M, Iemoli L, Rossoni G; Morazzoni P, Bombardelli E, Pietta P. Liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry of terpene lactones in plasma of animals. J Pharm Biomed Anal. 2003, 32(4-5): 633-9.
[100] Lo YL. Relationships between the hydrophilie-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. J Control Release. 2003, 90(1): 37-48.
[101] Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992, 22(1): 1-21.
[102] Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 1994, 26(2): 144-60.
[103] Dogra SC, Whitelaw ML, May BK. Transcriptional activation of cytochrome P450 genes by different classes of chemical inducers. Clin Exp Pharmacol Physiol. 1998, 25(1): 1-9.
[104] 胡云珍，姚彤炜．细胞色素P450 1A的研究进展．中国药学杂志．2003，38：246-50．
[105] 许振华，周宏灏．细胞色素氧化酶P450 1A2与药物代谢．中国临床药理学杂志．1996，12：115-21．
[106] 陈刚．治疗药物监测．北京：人民军医出版社．1988，358．
[107] Ohnishi A., Kato M., Kojima J., Ushiama H., Yoneko M., Kawai H. Differential pharmacokinetics of theophylline in elderly patients. Drugs..Aging. 2003, 20(1): 71-84.
[108] Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet. 1978, 3(4): 267-93.
[109] Grygiel JJ, Miners JO, Drew R, Birkett DJ. Differential effects of cimetidine on theophylline metabolic pathways. Eur J Clin Pharmacol. 1984, 26(3): 335-40.
[110] Campbell ME, Grant DM, Inaba T, Kalow W. Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos. 1987, 15(2): 237-49.
[111] Rogge MC, Solomon WR, Sedman AJ, Welling PC, Toothaker RD, Wagner JG. The theophylline-enoxacin interaction: Ⅰ. Effect of enoxacin dose size on theophylline disposition. Clin Pharmacol 7her. 1988, 44(5): 579-87.
[112] Gu L, Gonzalez FJ, Kalow W, Tang BK. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYPlA2 and CYP2E1. Pharmacogenetics. 1992, 2(2): 73-7.
[113] Sarkat MA, Hunt C, Guzelian PS, Karnes HT. Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos. 1992, 20(1): 31-7.
[114] Teunissen MW, Brorens IO, Geerlings JM, Breimer DD. Dose-dependent elimination of theophylline in rats.Xenobiotica. 1985, 15(2): 165-71.
[115] Crygiel JJ, Wing LM, Farkas J, Birkett DJ. Effects of allopurinol on theophylline metabolism and clearance. Clin Pharmacol Ther. 1979, 26(5): 660-7.
[116] Morimoto T, Kotegawa T, Tsutsumi K, Ohtani Y, Imai H, Nakano S. Effect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers. J Clin Pharmacol. 2004, 44(1): 95-101.
[117] Barnes PJ. Therapy of chronic obstructive pulmonary disease. Pharmacol Ther. 2003, 97(1): 87-94.
[118] Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995, Suppl 1: 20-5.
[119] Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implicatios. Am Fam Physician. 1998, 57(1): 107-16.
[120] Smith TJ, Guo Z, Guengerich FP, Yang CS. Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)by human cytochrome P450 1A2 and its inhibition by phenethyl isothiocyanate. Carcinogenesis. 1996, 17(4): 809-13.
[121] Bachmann K, Sanyal G, Potter J, Schiavone R, Loch J. In vivo evidence that theophylline is metabolized principally by CYP1A in rats. Pharmacology. 1993, 47(1): 1-7.
[122] Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992, 340(8828): 1136-9.
[123] Canivenc-Lavier MC, Vemevaut MF, Totis M, Siess MH, Magdalou J, Suschetet M. Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver. Toxicology. 1996, 114(1): 19-27.
[124] Siess MH, Mas JP, Canivenc-Lavier MC, Suschetet M. Time course of induction of rat hepatic drug-metabolizing enzyme activities following dietary administration of flavonoids. J Toxicol Environ Health. 1996, 49(5): 481-96.
[125] 杨秀芬，王乃平，曾繁典．银杏内酯对大鼠肝细胞色素P450基因表达的影响．中国中药杂志．2005，30：1009-13，
[126] Balimane PV, Patel K, Marino A, Chong S. Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery. Eur J Pharm Biopharm. 2004, 58(1): 99-105.
[127] Takara K, Tsujimoto M, Ohnishi N, Yokoyama T. Digoxin up-regulates MDR1 in human colon carcinoma Caco-2 cells. Biochem Biophys Res Commun. 2002, 292(1): 190-4.
[128] Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res. 2002, 19(6): 765-72.
[129] Choi CH, Kim JH, Kim SH. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR. Biochem Biophys Res Commun. 2004, 320(3): 672-9.
[130] Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001, 299(2): 620-8.
[131] Berggren S, Heogstraate J, Fagerholm U, Lennernas H. Characterization of jejunal absorption and apical efflux of ropivacalne, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models. Eur JPharm Sci. 2004, 21(4): 553-60.
[132] Doppenschmitt S, Spahn-Langguth H, Regardh CG, Langguth P. Radioligand-binding assay employing P-glycoprotein-overexpressing cells: testing drug affinities to the secretory intestinal multidrug transporter. Pharm Res. 1998, 15(7): 1001-6.
[133] Garrigues A, Nugier J, Orlowski S, Ezan E. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal Biochem. 2002, 305(1): 106-14.
[134] Schmid D, Ecker G, Kopp S, Hitzler M, Chiba P. Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol. 1999, 58(9): 1447-56.
[135] Meyer S, Noisommit-Rizzi N, Reuss M, Neubauer P. Optimized analysis of intracellular adenosine and guanosine phosphates in Escherichia coli. Anal Biochem. 1999, 271(1): 43-52.
[136] Pento JT, Mousissian GK. Time-dependent deterioration of active transport in duodenal segments of rat intestine. J Pharmacol Methods. 1988, 20(1): 9-14.
[137] Barthe L, Woodley JF, Kenworthy S, Houin G. An improved everted gut sac as a simple and accurate technique to measure paracellular transport across the small intestine. Eur J Drug Metab Pharmacokinet. 1998, 23(2): 313-23.
[138] Mauro VF, Mauro LS, Kleshinski JF, Khuder SA, Wang Y, Erhardt PW. Impact of ginkgo biloba on the pharmacokinetics of digoxin. Am J Ther. 2003, 10(4): 247-51.
[139] Perloff MD, von Moltke LL, Greenblatt DJ. Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol. 2002, 42(11): 1269-74.
[140] Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001, 69(3): 114-21.
[141] Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John's wort on the phatmacokinefics of fexofenadine. Clin Pharmacol Ther. 2002, 71(6): 414-20.
[142] Davit B, Reynolds K, Yuan R, Ajayi F, Conner D, Fadiran E, Gillespie B, Sahajwalla C, Huang SM, Lesko LJ. FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling. J Clin Pharmacol. 1999, 39(9): 899-910.
[143] Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther. 2001, 23(3): 451-66.
[144] Hartmann C, Krauss D, Spahn H, Mutschler E. Simultaneous determination of (R)- and (S)-celiprolol in human plasma and urine: high-performance liquid chromatographic assay on a chiral stationary phase with fluorimetric detection. J Chromatogr. 1989, 496(2): 387-96.
[145] Hitzenberger, G, Takaca, F., Pittner, H., 1983. Pharmakokinetik des P-Rezeptorenblockers Celiprolol nach einmaliger intraventiser und oraler Gabe. Arzneim: Forsch./Drug. Res. 33(1), 50-2.
[146] Lipka E, Spahn-Langguth H, Mutschler E, Amidon GL. In vivo non-linear intestinal permeability of celiprolol and propranolol in conscious dogs: evidence for intestinal secretion. Eur J Pharm Sci. 1998, 6(1): 75-81.
[147] Karlsson J, Kuo SM, Ziemniak J, Artursson P. Transport of celiprolol across human intestinal epithelial(Caco-2)cells: mediation of secretion by multiple transporters including P-glyeoprotein. Br J Pharmacol. 1993, 110(3): 1009-16.
[148] Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Honin G, Impact of excipients on the absorption of P-glyeoprotein substrates in vitro and in vivo. Int J Pharm. 2004, 278(1): 119-31.
[149] 平其能等．现化药剂学．北京．中国医药科技出版社．1998：177-87．
[150] Petal N, Tannergren C, Rungstad D, Lennemas H. Transport characteristics of fexofenadine in the Caco-2 cell model. Pharm Res. 2004, 21(8): 1398-404.
[151] Tian R, Koyabu N, Takanaga H, Matsuo H, Ohtani H, Sawada Y. Effects of grapefruit juice and orange juice on the intestinal effiux of P-glyeoprotein substrates. Pharm Res. 2002, 19(6): 802-9.
[152] Jonker C, Hamman JH, Kotze AF. Intestinal paracellular permeation enhancement with quatemised chitosan: in situ and in vitro evaluation. Int J Pharm. 2002, 238(1-2): 205-13.
[153] Tomei S, Torimoto M, Hayashi Y, Inoue K, Yuasa H, Watanabe J. Kinetic characterization of carrier-mediated transport systems for D-glucose and taurocholate in the everted sacs of the rat colon. Biol Pharm Bull. 2003, 26(6): 899-901.
[154] Kitagawa S, Nabekura T, Takahashi T, Nakamura Y, Sakamoto H, Tano H, Hirai M, Tsukahara G. Structure-activity relationships of the inhibitory effects of flavonoids on P-glyeoprotein-mediated transport in KB-C2 cells. Biol Pharm Bull. 2005, 28(12): 2274-8.
[155] Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. lnt J Pharm. 2006, 313(1-2): 144-9.
[156] Wang Y, Cao J, Zeng S. Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin. J Pharm Pharmacol. 2005, 57(6): 751-8.
[157] ofer M, Wolffram S, Koggel A, Spahn-Langguth H, Langguth P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur J Pharm Sci. 2005, 25(2-3): 263-71.
[158] Yang ZG, Meng H, Zhang X, Li XD, Lv WL, Zhang Q. Effect of quercetin on the aeyelovir intestinal absorption. Beijing Da Xue Xue Bao. 2004, 36(3): 309-12.