非索非那定体内探针法考察多剂量黄芪颗粒对人体P-gp活性影响的随机、安慰剂对照研究
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摘要
目的：
1.探讨黄芪颗粒对人体P-gp活性的影响,以预期黄芪颗粒与常见合并用药相互作用的临床可能性；
2.考察在中国人中MDR1 C3435T和SLCO1B1 T521C基因多态性对非索非那定(FEX)药动学的影响；
3.考察黄芪颗粒对MDR1 C3435T和SLCO1B1 T521C不同基因亚组的影响。
方法：
1.首先建立FEX血浆浓度的测定方法。以乙腈直接沉淀法处理200μl血浆样品,高速离心后上清液吹干,复溶后直接进样分析。分析柱：Waters Symmetry C18色谱柱(4.6mm×250mm,5μm);流动相：0.1mol·L-1醋酸铵溶液-乙腈(63：37,v／v)；流速：1mL·min-1;检测器：荧光检测器(激发波长为230nm,发射波长为290nm)；以苯海拉明为内标,用内标法定量,进行色谱确证试验。
2.设计一项随机、双周期、安慰剂对照临床试验,以FEX药动学参数作为人体内P-gp活性的探针。14名健康男性志愿者随机口服黄芪颗粒(4g bid)或安慰剂(4g bid),多剂量连续服用一周后,服用探针药物FEX片120mg,采集不同时间点的血浆,经色谱测定和DAS2.1.1统计软件分析,选择非房室模型计算药动学参数,并进行生物等效性统计分析。比较安慰剂组与黄芪组中FEX的药动学差异。
3.利用黄芪颗粒-FEX相互作用研究中志愿者全血样本,检测MDR1 C3435T和SLCO1B1 T521C两个位点的突变情况,对不同基因型亚组中的FEX药动学参数进行数据挖掘。
结果：
1.本研究建立的色谱方法专属性强。在20-1000μg/L浓度范围内线性良好(r=0.9993,n=5)。定量限为20μg/L。高、中、低质控样品的日内、日间RSD均小于10%,方法学回收率为105.9%,提取回收率为94.6%。
2.在安慰剂组中,FEX的药动学参数：T1/2 3.75±1.47h; Cmax 745.1±137.41μg/L; Tmax 2.25±0.47h; AUC(0-t) 3894.27±923.45μg/L*h; AUC(0-∞)3993.84±912.97μg/L*h.在黄芪颗粒组中,FEX的药动学参数：T1/2 4.00±1.24h; Cmax 709.44±170.03μg/L; Tmax 2.21±0.51h; AUC(0-t) 3832.72±1077.60μg/L*h; AUC(0-∞)3983.53±1019.83μg/L*h.黄芪颗粒对FEX的药动学影响无统计学意义(P>0.05)。FEX片在服用安慰剂组和服用黄芪颗粒组中人体内生物等效。与国外文献报道相比较,发现Cmax、Tmax和AUC0～t的差异无统计学意义(P<0.05),T1／2与国内文献报道值(5.34±1.15h)较为接近,但小于国外文献报道的9.6±2.9h。
3.14名健康志愿者中MDR1 C3435T基因型的分型结果：野生型纯合子CC(n=5)；突变型纯合子TT(n=3)、突变型杂合子CT (n=6). OATP1B1 T521C基因型分型结果：TT (n=12); TC (n=2).
4.MDR1 C3435T基因型与非索非那定药动学关系：突变基因T携带者中,FEX的T1／2要高于野生型CC基因型携带者中的数据(TT、CT、TT+CT> CC, P<0.01).在黄芪组中,未观察到T1／2的基因剂量效应(TT、CT、TT+CT> CC→TT、CT、TT+CT=CC, P>0.05).通过比较安慰剂组和黄芪组中相应CC基因型的药动学参数,发现T1／2的差异具有统计学意义(P<0.05,T1/2安慰剂 5.FEX在安慰剂组中的PK参数并没有呈现OATP1B1 T521C的基因剂量效应。黄芪颗粒预处理后,与OATP1B1 521TT野生型纯合子相比,突变型杂合体(CT)携带者中的Cmax有升高迹象(889.50±11.54 vs 679.43±158.09μg/L, P=0.05).
结论：
1.本实验建立的RP-HPLC法快速简便、灵敏、专属、准确,可用于FEX的临床药动学研究；
2.黄芪颗粒预处理一周不会显著影响人体P-gp活性,但它的影响具有MDR1C3435T基因型依赖性。在MDR1 C3435T基因型分亚组的情况下,显示了黄芪颗粒对P-gp的影响。黄芪颗粒对野生型等位基因个体中的P-gp有一定的抑制作用。野生型个体中的P-gp受到的抑制作用程度要大于突变型个体中P-gp受到的抑制作用程度。
3.FEX消除速率可能存在民族差异性,值得进一步研究。
4.黄芪颗粒预处理一周对中国健康志愿者的OATP1B1活性可能有抑制作用。
Objective:
1. To investigate the influences of Astragalus root extract (Huang Qi) granules on human P-gp and anticipate the risk of its drug interactions with common coadministered medications;
2. To investigate the effects of MDR1 C3435T and SLCO1B1 T521C polymorphism on fexofenadine (FEX) pharmacokinetics and whether pretreatment of Huang Qi granules produces different effects on subgroup of C3435T or T521C genotype.
Methods:
1. An assay method was established for determining FEX concentrations in human plasma. Plasma samples(200μL) were deproteinized by precipitation with acetonitrile, centrifuged and the supernatant was reconstituted and injected into HPLC. Separation was achieved on Waters Symmetry C18 (4.6mm×250mm,5μm) with a mixture of 0.1mol/L ammonium acetate-acetonitrile (63:37, v/v) as mobile phase. The flow rate was 1mL/min. The fluorescence detector was set at excitation wavelength of 230 nm and emission wavelength of 290 nm. The internal standard method was used to quantify Fex. The assay was validated and applied to pharmacokinetic study.
2. The study had an open-label, randomized, placebo-controlled, two-period crossover design, with 3 wk washout between periods. Fex was used as an in vivo P-gp phenotyping probe.Fourteen volunteers received multiple doses of Huang Qi granules (4 g bid) or placebo (4 g bid) for one week and then received a single oral dose of 120 mg FEX tablet. Plasma samples were taken at different times and analysed by chromatography. Pharmacokinetic parameters were calculated by non-compartmental method and compared in two groups. Bioequivalence evaluation was performed by the software DAS2.1.1.
3. C3435T mutation in exon 26 (MDR1 C3435T) and SLCO1B1 T521C mutation were determined in this pharmacokinetic study. Data mining was performed.
Results:
1. With respect to chromatographic analysis, endogenous chemicals did not interfere with Fex. The calibration curves were linear in the range of 20～1000μg/L (r=0.9993, n=5), with a limit of quantitation of 20μg/L. The within-and between-day RSDs of quality-control samples at high-, medium-and low-concentrations were less than 10%. The average method recovery was 105.9%. The average absolute recovery was 94.6%.
2. Pharamcokinetic parameters derived from placebo group were as follows:T1/2(3.75±1.47 h); Cmax (745.11±137.41μg/L); Tmax (2.25±0.47 h); AUC(0-t) (3894.27±923.45μg/L*h); AUC(0-∞) (3993.84±912.97μg/L*h).Pharamcokinetic parameters derived from Huang Qi group were as follows::T1/2(4.00±1.24 h); Cmax(709.44±170.03μg/L); Tmax (2.21±0.51 h); AUC(0-t) (3832.72±1077.60μg/L*h); AUC(0-∞) (3983.53±1019.83μg/L*h). The effects of Hunag Qi granules on FEX pharmcokinetics were insignificant (P>0.05). FEX tablets in two groups were bioequivalent. The average elimination half life was similar with data derived from Liu's study in 20 Chinese volunteers, but it was shorter than documented data (9.6±2.9 h) abroad. With respect to Cmax, Tmax and AUCo-t, no significant differences were obversed(P<0.05).
3. MDR1 C3435T phenotyping results of 14 healthy volunteers were as follows: hemozygous CC (wide type, n=5); hemozygous TT(mutation type,n=3); heterozygous CT(mutation type,n=6). OATP1B1 T521C phenotyping results were as follows:TT(n=12); TC (n=2).
4. In MDR1 3435 T allele carriers, T1/2 of FEX was longer than that in MDR1 3435 CC carriers (TT, CT, TT+CT> CC, P<0.01). Gene-dose effects on T1/2 in Huang Qi group were not observed (TT, CT, TT+CT> CC→TT, CT, TT+CT=CC, P> 0.05). By comparison of pharmacokinetic parameters in MDR1 3435 CC carriers in either placebo group or Huang Qi group, difference in T1/2 was significant(P=0.02, T1/2(Placebo)< T1/2(Huangqi)).
5. There were no gene-dose effects of OATP1B1 521 C on pharmacokinetic parameters of fexofenadine in placebo group. Cmax in OATPIB1 521 C allele carriers exhibited an increase trend with marginal significance (889.50±11.54 vs 679.43±158.09μg/L, P=0.05) compared with that in OATP1B1 521 TT carriers.
Conclusion:
1. The RP-HPLC assay is stable, simple, rapid, accurate, sensitive and applicable for determining plasma concentrations of FEX in its pharmacokinetic studies;
2. One-week pretreatment of Huang Qi granules has no significant effects on human P-gp activity in Chinese healthy subjects. However, effect of Huang Qi granules on P-gp was MDR1 C3435T genotype-dependent. Huang Qi granules may have inhibitory effects on P-gp activity in MDR1 3435 CC carriers. The decrement degree in 3435 CC carriers was greater than that in 3435 T allele carriers.
3. The terminal elimination profile of FEX indicates ethnic differences and further investigation is needed.
4. One-week pretreatment of Huang Qi granules may have inhibitory effects on OATP1B1 activity in Chinese healthy subjects.
1.探讨黄芪颗粒对人体P-gp活性的影响,以预期黄芪颗粒与常见合并用药相互作用的临床可能性；
2.考察在中国人中MDR1 C3435T和SLCO1B1 T521C基因多态性对非索非那定(FEX)药动学的影响；
3.考察黄芪颗粒对MDR1 C3435T和SLCO1B1 T521C不同基因亚组的影响。
方法：
1.首先建立FEX血浆浓度的测定方法。以乙腈直接沉淀法处理200μl血浆样品,高速离心后上清液吹干,复溶后直接进样分析。分析柱：Waters Symmetry C18色谱柱(4.6mm×250mm,5μm);流动相：0.1mol·L-1醋酸铵溶液-乙腈(63：37,v／v)；流速：1mL·min-1;检测器：荧光检测器(激发波长为230nm,发射波长为290nm)；以苯海拉明为内标,用内标法定量,进行色谱确证试验。
2.设计一项随机、双周期、安慰剂对照临床试验,以FEX药动学参数作为人体内P-gp活性的探针。14名健康男性志愿者随机口服黄芪颗粒(4g bid)或安慰剂(4g bid),多剂量连续服用一周后,服用探针药物FEX片120mg,采集不同时间点的血浆,经色谱测定和DAS2.1.1统计软件分析,选择非房室模型计算药动学参数,并进行生物等效性统计分析。比较安慰剂组与黄芪组中FEX的药动学差异。
3.利用黄芪颗粒-FEX相互作用研究中志愿者全血样本,检测MDR1 C3435T和SLCO1B1 T521C两个位点的突变情况,对不同基因型亚组中的FEX药动学参数进行数据挖掘。
结果：
1.本研究建立的色谱方法专属性强。在20-1000μg/L浓度范围内线性良好(r=0.9993,n=5)。定量限为20μg/L。高、中、低质控样品的日内、日间RSD均小于10%,方法学回收率为105.9%,提取回收率为94.6%。
2.在安慰剂组中,FEX的药动学参数：T1/2 3.75±1.47h; Cmax 745.1±137.41μg/L; Tmax 2.25±0.47h; AUC(0-t) 3894.27±923.45μg/L*h; AUC(0-∞)3993.84±912.97μg/L*h.在黄芪颗粒组中,FEX的药动学参数：T1/2 4.00±1.24h; Cmax 709.44±170.03μg/L; Tmax 2.21±0.51h; AUC(0-t) 3832.72±1077.60μg/L*h; AUC(0-∞)3983.53±1019.83μg/L*h.黄芪颗粒对FEX的药动学影响无统计学意义(P>0.05)。FEX片在服用安慰剂组和服用黄芪颗粒组中人体内生物等效。与国外文献报道相比较,发现Cmax、Tmax和AUC0～t的差异无统计学意义(P<0.05),T1／2与国内文献报道值(5.34±1.15h)较为接近,但小于国外文献报道的9.6±2.9h。
3.14名健康志愿者中MDR1 C3435T基因型的分型结果：野生型纯合子CC(n=5)；突变型纯合子TT(n=3)、突变型杂合子CT (n=6). OATP1B1 T521C基因型分型结果：TT (n=12); TC (n=2).
4.MDR1 C3435T基因型与非索非那定药动学关系：突变基因T携带者中,FEX的T1／2要高于野生型CC基因型携带者中的数据(TT、CT、TT+CT> CC, P<0.01).在黄芪组中,未观察到T1／2的基因剂量效应(TT、CT、TT+CT> CC→TT、CT、TT+CT=CC, P>0.05).通过比较安慰剂组和黄芪组中相应CC基因型的药动学参数,发现T1／2的差异具有统计学意义(P<0.05,T1/2安慰剂
结论：
1.本实验建立的RP-HPLC法快速简便、灵敏、专属、准确,可用于FEX的临床药动学研究；
2.黄芪颗粒预处理一周不会显著影响人体P-gp活性,但它的影响具有MDR1C3435T基因型依赖性。在MDR1 C3435T基因型分亚组的情况下,显示了黄芪颗粒对P-gp的影响。黄芪颗粒对野生型等位基因个体中的P-gp有一定的抑制作用。野生型个体中的P-gp受到的抑制作用程度要大于突变型个体中P-gp受到的抑制作用程度。
3.FEX消除速率可能存在民族差异性,值得进一步研究。
4.黄芪颗粒预处理一周对中国健康志愿者的OATP1B1活性可能有抑制作用。
Objective:
1. To investigate the influences of Astragalus root extract (Huang Qi) granules on human P-gp and anticipate the risk of its drug interactions with common coadministered medications;
2. To investigate the effects of MDR1 C3435T and SLCO1B1 T521C polymorphism on fexofenadine (FEX) pharmacokinetics and whether pretreatment of Huang Qi granules produces different effects on subgroup of C3435T or T521C genotype.
Methods:
1. An assay method was established for determining FEX concentrations in human plasma. Plasma samples(200μL) were deproteinized by precipitation with acetonitrile, centrifuged and the supernatant was reconstituted and injected into HPLC. Separation was achieved on Waters Symmetry C18 (4.6mm×250mm,5μm) with a mixture of 0.1mol/L ammonium acetate-acetonitrile (63:37, v/v) as mobile phase. The flow rate was 1mL/min. The fluorescence detector was set at excitation wavelength of 230 nm and emission wavelength of 290 nm. The internal standard method was used to quantify Fex. The assay was validated and applied to pharmacokinetic study.
2. The study had an open-label, randomized, placebo-controlled, two-period crossover design, with 3 wk washout between periods. Fex was used as an in vivo P-gp phenotyping probe.Fourteen volunteers received multiple doses of Huang Qi granules (4 g bid) or placebo (4 g bid) for one week and then received a single oral dose of 120 mg FEX tablet. Plasma samples were taken at different times and analysed by chromatography. Pharmacokinetic parameters were calculated by non-compartmental method and compared in two groups. Bioequivalence evaluation was performed by the software DAS2.1.1.
3. C3435T mutation in exon 26 (MDR1 C3435T) and SLCO1B1 T521C mutation were determined in this pharmacokinetic study. Data mining was performed.
Results:
1. With respect to chromatographic analysis, endogenous chemicals did not interfere with Fex. The calibration curves were linear in the range of 20～1000μg/L (r=0.9993, n=5), with a limit of quantitation of 20μg/L. The within-and between-day RSDs of quality-control samples at high-, medium-and low-concentrations were less than 10%. The average method recovery was 105.9%. The average absolute recovery was 94.6%.
2. Pharamcokinetic parameters derived from placebo group were as follows:T1/2(3.75±1.47 h); Cmax (745.11±137.41μg/L); Tmax (2.25±0.47 h); AUC(0-t) (3894.27±923.45μg/L*h); AUC(0-∞) (3993.84±912.97μg/L*h).Pharamcokinetic parameters derived from Huang Qi group were as follows::T1/2(4.00±1.24 h); Cmax(709.44±170.03μg/L); Tmax (2.21±0.51 h); AUC(0-t) (3832.72±1077.60μg/L*h); AUC(0-∞) (3983.53±1019.83μg/L*h). The effects of Hunag Qi granules on FEX pharmcokinetics were insignificant (P>0.05). FEX tablets in two groups were bioequivalent. The average elimination half life was similar with data derived from Liu's study in 20 Chinese volunteers, but it was shorter than documented data (9.6±2.9 h) abroad. With respect to Cmax, Tmax and AUCo-t, no significant differences were obversed(P<0.05).
3. MDR1 C3435T phenotyping results of 14 healthy volunteers were as follows: hemozygous CC (wide type, n=5); hemozygous TT(mutation type,n=3); heterozygous CT(mutation type,n=6). OATP1B1 T521C phenotyping results were as follows:TT(n=12); TC (n=2).
4. In MDR1 3435 T allele carriers, T1/2 of FEX was longer than that in MDR1 3435 CC carriers (TT, CT, TT+CT> CC, P<0.01). Gene-dose effects on T1/2 in Huang Qi group were not observed (TT, CT, TT+CT> CC→TT, CT, TT+CT=CC, P> 0.05). By comparison of pharmacokinetic parameters in MDR1 3435 CC carriers in either placebo group or Huang Qi group, difference in T1/2 was significant(P=0.02, T1/2(Placebo)< T1/2(Huangqi)).
5. There were no gene-dose effects of OATP1B1 521 C on pharmacokinetic parameters of fexofenadine in placebo group. Cmax in OATPIB1 521 C allele carriers exhibited an increase trend with marginal significance (889.50±11.54 vs 679.43±158.09μg/L, P=0.05) compared with that in OATP1B1 521 TT carriers.
Conclusion:
1. The RP-HPLC assay is stable, simple, rapid, accurate, sensitive and applicable for determining plasma concentrations of FEX in its pharmacokinetic studies;
2. One-week pretreatment of Huang Qi granules has no significant effects on human P-gp activity in Chinese healthy subjects. However, effect of Huang Qi granules on P-gp was MDR1 C3435T genotype-dependent. Huang Qi granules may have inhibitory effects on P-gp activity in MDR1 3435 CC carriers. The decrement degree in 3435 CC carriers was greater than that in 3435 T allele carriers.
3. The terminal elimination profile of FEX indicates ethnic differences and further investigation is needed.
4. One-week pretreatment of Huang Qi granules may have inhibitory effects on OATP1B1 activity in Chinese healthy subjects.
引文
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3 Zimmerman CL, Slattery JT. Maintenance-dose prediction based on a single determination of concentration:general applicability to two-compartment drugs with reference to lithium. J Pharm Sci,1983,72:1262-1266.
4 Lin YS, Lockwood GF, Graham MA, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics, 2001,11(9):781-791.
5 Eap CB, Buclin T, Cucchia G, et al. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol,2004,60(4):237-246.
6 Gurley B, Hubbard MA, Williams DK, et al. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity:Comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol,2006,46(2):201-213.
7 Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos,2003,31(11):1283-1287.
8 Hu Z, Gong Q, Hu X, et al. Simultaneous determination of 6beta-hydroxycortisol and cortisol in human urine and plasma by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity [J]. J Chromatogr B Analyt Technol Biomed Life Sci,2005,826(1-2):238-243.
9 尧臣彬,李坤艳,李焕德.内源性氢化可的松为探针的CYP3A活性测定.中南药学,2006,4(2)：104-106.
10 Rouits E, Boisdron-Celle M, Morel A, et al. SRouits E, Boisdron-Celle M, Morel A, Gamelin E. Simple and sensitive high-performance liquid chromatography method for simultaneous determination of urinary free cortisol and 6beta-hydroxycortisol in routine practice. For CYP3A4 activity evaluation in basal conditions and after grapefruit juice intake. J Chromatogr B Analyt Technol Biomed Life Sci, 2003,793(2):357-366.
11 Kawaguchi A, Ohmori M, Tsuruoka S, et al. Drug interaction between St John's Wort and quazepam. Br J Clin Pharmacol,2004,58 (4),403-410.
12 Barrett YC, Akinsanya B, Chang SY, et al. Automated on-line SPE LC-MS/MS method to quantitate 6beta-hydroxycortisol and cortisol in human urine:use of the 6beta-hydroxycortisol to cortisol ratio as an indicator of CYP3A4 activity. J Chromatogr B Analyt Technol Biomed Life Sci,2005,821(2):159-165.
13 Furuta T, Mori C, Suzuki A, et al. Simultaneous determination of 6beta-hydroxycortisol and cortisol in human urine by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3 A activity determined by the cortisol 6beta-hydroxylation clearance. J Chromatogr B Analyt Technol Biomed Life Sci,2004,801(2):165-171.
14 Chen YC, Gotzkowsky SK, Nafziger AN, et al. Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br J Clin Pharmacol,2006,62(2):187-195.
15 Wieling J, Tamminga WJ, Sakiman EP, et al. Wieling J, Tamminga WJ, Sakiman EP, Oosterhuis B, Wemer J, Jonkman JH. Evaluation of analytical and clinical performance of a dual-probe phenotyping method for CYP2D6 polymorphism and CYP3A4 activity screening. Ther Drug Monit,2000,22(4):486-496.
16 Kuo BP, Hu OY, Hsiong CH, et al. Single-point plasma or urine dextromethorphan method for determining CYP3A activity [J]. Biopharm Drug Dispos,2003, 24(9):367-373.
17 Kashuba AD, Nafziger AN, Kearns GL, et al. Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity. Pharmacogenetics, 1999,9(4):453-462.
18 Drabant S, Toth M, Bereczki A, et al. Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug alprazolam. Eur J Clin Pharmacol,2006,62(7):587-588.
19 Wennerholm A, Allqvist A, Svensson JO, et al. Alprazolam as a probe for CYP3A using a single blood sample:pharmacokinetics of parent drug, and of alpha-and 4-hydroxy metabolites in healthy subjects. Eur J Clin Pharmacol,2005, 61(2):113-118.
20 [FDA/CDER]Food and Drug Administration/Center for Drug Evaluation and Research (1999) Guidance for industry:in vivo drug metabolism/drug interaction studies:study design, data analysis and recommendations for dosing and labeling. Oct 6,1999. Center for Drug Evaluation and Research, Rockville, MD.
21 Laine K, Ahokoski O, Huupponen R, et al. Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone. Eur J Clin Pharmacol,2003,59(10):761-766.
22 Dresser GK, Wacher V, Wong S, et al. Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo. Clin Pharmacol Ther,2002,72(3),247-255
23 MF Paine, WW Widmer, HL Hart, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutri,2006,83(5):1097-1105
24 Sugimoto K, Ohmori M, Tsuruoka S, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther, 2001,70(6):518-524.
25 Chung E, Nafziger AN, Kazierad DJ, et al. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther,2006, 79(4):350-361.
26 Wanwimolruk S, Paine MF, Pusek SN, et al. Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4? Br J Clin Pharmacol, 2002,54(6):643-651.
27 Paine MF, Wagner DA, Hoffmaster KA, et al. Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin. Clin Pharmacol Ther,2002,72(5):524-535.
28 Bottiger Y. Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4. Eur J Clin Pharmacol,2006,62(8):621-625.
29 Yin OQ, Tomlinson B, Waye MM, et al. Pharmacogenetics and herb-drug interactions:experience with Ginkgo biloba and omeprazole. Pharmacogenetics, 2004,14(12):841-50.
30 Kharasch ED, Russell M, Garton K, et al. Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Anesthesiology,1997,87(1):26-35.
31 Kharasch ED, Walker A, Hoffer C, et al. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity:noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther,2004,76(5):452-466.
32 Lowry JA, Kearns GL, Abdel-Rahman SM, et al. Cisapride:a potential model substrate to assess cytochrome P4503A4 activity in vivo. Clin Pharmacol Ther, 2003,73(3):209-222.
33 Damkier P, Brosen K. Quinidine as a probe for CYP3A4 activity:intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Clin Pharmacol Ther,2000,68(2):199-209.
34 Xie HJ, Yasar U, Sandberg M, et al. Paeoniae Radix, a traditional Chinese medicine, and CYP2C9 activity. J Clin Pharm Ther,2002,27 (3):2291
35 Mohutsky MA, Anderson GD, Miller JW, et al. Ginkgo biloba:evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther,2006,13(1):24-31.
36 Greenblatt DJ, von Moltke LL, Luo Y, et al. Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol,2006,46 (2):214-221.
37杨秋慧,孟宪清,李玉兰.复方丹参诱导人体P4501A2作用观察.哈尔滨医科大学学报,1997,31(4)：295-296.
38苗丽娟,孟宪清.刺五加对大鼠及人肝微粒体酶CYP450的作用观察.哈尔滨医科大学学报,1998,32(5)：336-339.
39周权.代谢性药物相互作用.见：曾苏.药物代谢学[M].第一版.杭州：浙江大学出版社,2004.
40 Saruwatari J, Nakagawa K, Shindo J, et al. The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man. J Pharm Pharmacol,200,55(11):1553-1559.
41 Schmider J, Brockmoller J, Arold G, et al. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics, 1999,9(6):725-734.
42 Donovan JL, DeVane CL, Chavin KD, et al. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos,2003,31(5):519-522.
43 Markowitz JS, Donovan JL, Lindsay DeVane C, et al. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol,2003,23(6):576-581.
44 Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos, 2004,32(12):1333-1336.
45程泽能,张毕奎,李菲,等.中药止咳橘红颗粒对CYP3A4和CYP1A2抑制作用的研究.中国临床药理学杂志,2002,18(3)：215-218.
46 Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther,2002, 72(3):276-287.
47 Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2,2D6,2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther,2005,77(5):415-426.
48 Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes:Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther, 2004,76(5):428-40.
49 Gorski JC, Huang SM, Pinto A, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther, 2004,75(1):89-100.
50 Sun H, Zuo Z, Yin OQ, et al. A"high-throughput"cocktail method for screening the effect of herbal product on liver isoenzyme activities:experience with Ginkgo Biloba. Clin Pharmacol Ther,2002,71(2):1001.
51 Chow HH, Hakim IA, Vining DR, et al. Effects of Repeated Green Tea Catechin Administration on Human Cytochrome P450 Activity. Cancer Epidemiol Biomarkers Prev,2006,15(12):2473-2476.
52 Chen XP, Tan ZR, Huang SL, et al. Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clin Pharmacol Ther,2003,73(3):264-271.
53 Chainuvati S, Nafziger AN, Leeder JS, et al. Combined phenotypic assessment of cytochrome p450 1A2,2C9,2C19,2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Clin Pharmacol Ther,2003,74(5):437-447.
54 Yin OQ, Lam SS, Lo CM, et al. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry:application to cytochrome P450 phenotyping studies. Rapid Commun Mass Spectrom,2004,18(23):2921-2933.
55 Christensen M, Andersson K, Dalen P, et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther,2003, 73(6):517-528.
56 Mark Muzi, David A. Mankoff, Jeanne M. Link et al. Imaging of Cyclosporine Inhibition of P-Glycoprotein Activity Using 11C-Verapamil in the Brain:Studies of Healthy Humans. J Nucl Med,2009,50(8):1267-1275.
57 Kim KA, Park PW, Park JY. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol,2009,65(6):609-14.
58. Robertson SM, Davey RT, Voell J, et al. Effect of Gingko Biloba extract on lopinavir, midazolam, and fexofenadine pharmacokinetics in healthy subjects [J]. Curr Med Res Opin,2008,24(2):591-599.
59. Gurley BJ, Barone GW, Williams DK, Carrier J, Breen P, Yates CR, Song PF, Hubbard MA, Tong Y, Cheboyina S. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos,2006,34(1):69-74.
60. Parker RB, Yates CR, Soberman JE,, et al Effects of grapefruit juice on intestinal P-glycoprotein:evaluation using digoxin in humans. Pharmacotherapy,2003, 23(8):979-987.
61. Johne A, Brockmoller J, Bauer S, et al Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther,1999,66(4):338-345.
62. Kirby B, Kharasch ED, Thummel KT, et al. Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities [J]. J Clin Pharmacol, 2006,46(11):1313-1319.
63. Reed GA, Sunega JM, Peterson KS. Probe drug investigations suggest no pharmacokinetic interactions with ginseng and ginkgo biloba supplements [J]. FASEB J,2007,21:891.
64. Di Marco MP, Edwards DJ, Wainer IW, et al. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan:the role of gut CYP3A and P-glycoprotein [J]. Life Sci,2002,71(10):1149-1160.
2. 周权.药物代谢动力学与药物相互作用.曾苏主编.临床药物代谢动力学.人民卫生出版社,2007.
3. Zhou SF, Zhou ZW, Li CG, et al. Identification of drugs that interact with herbs in drug development. Drug Discov Today 2007; 12:664-73
4. De Smet PA. Clinical risk management of herb-drug interactions. Br J Clin Pharmacol 2007; 63:258-67
5. Izzo AA. Herb-drug interactions:an overview of the clinical evidence. Fundam Clin Pharmacol 2005; 19:1-16
6. Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications:a clinical survey. Alternat Ther Health Med 2007; 13:30-5
7.57 Kim KA, Park PW, Park JY. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein, in healthy volunteers. Eur J Clin Pharmacol,2009,65(6):609-14.
8.58. Robertson SM, Davey RT, Voell J, et al. Effect of Gingko Biloba extract on lopinavir, midazolam, and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin,2008,24(2):591-599.
9. Niemi M, Kivisto KT, Hofmann U, et al. Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol,2005,59(5):602-4.
10. NIROGI R V, KANDIKERE V N, SHUKLA M, et al. Quantification of fexofenadine in human plasma by liquid chromatography coupled to electrospray tandem mass spectrometry using mosapride as internal standard. J Biomed Chromatogr,2007,21(2):209-216.
11. YAMANE N, TOZUKA Z, SUGIYAMA Y, et al. Microdose clinical trial: Quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry. J Chromatogr B,2007,858(1-2):118-128.
12. UNO T, YASUI-FURUKORI N, TAKAHATA T, et al. Liquid chromatographic determination of fexofenadine in human plasma with fluorescence detection. J Pharm Biomed Anal,2004,35(4):937-942.
13.刘茜,刘翠,尚宏伟.盐酸非索非那定胶囊药物动力学及人体相对生物利用度研究.2007,27(11)：1707-1710.
14. AZARPIRA N, AGHDAIE MH. Frequency of C3435 MDR1 and A6896G CYP3A5 Single Nucleotide Polymorphism in an Iranian Population and Comparison with Other Ethnic Groups. MJIRI,2006,20(3):131-136.
15. Kwan P, Baum L, Wong V, Ng PW, et al.Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. Epilepsy Behav,2007,11(1):112-7.
16. Kalliokoski A, Neuvonen M, Neuvonen PJ, et al. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol.2008,66(6):818-25.
17. Romaine SP, Bailey KM, Hall AS, et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J,2010,10(1):1-11.
18.张伟,贺毅憬,周宏灏.有机阴离子转运多肽181的遗传药理学进展.中国临床药理杂志,2008,13(7)：721-729.
19. Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos,2005,33(10):1477-81.
1 周权,徐庆,寿军,等.植物药与西药的药动学相互作用.中国药学杂志,2004,39(12)：884-887.
2 Mueller SC, Majcher-Peszynska J, Uehleke B, et al. The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose. Eur J Clin Pharmacol,2006,62(1):29-36.
3 Zimmerman CL, Slattery JT. Maintenance-dose prediction based on a single determination of concentration:general applicability to two-compartment drugs with reference to lithium. J Pharm Sci,1983,72:1262-1266.
4 Lin YS, Lockwood GF, Graham MA, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics, 2001,11(9):781-791.
5 Eap CB, Buclin T, Cucchia G, et al. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol,2004,60(4):237-246.
6 Gurley B, Hubbard MA, Williams DK, et al. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity:Comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol,2006,46(2):201-213.
7 Furuta T, Suzuki A, Mori C, et al. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos,2003,31(11):1283-1287.
8 Hu Z, Gong Q, Hu X, et al. Simultaneous determination of 6beta-hydroxycortisol and cortisol in human urine and plasma by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity [J]. J Chromatogr B Analyt Technol Biomed Life Sci,2005,826(1-2):238-243.
9 尧臣彬,李坤艳,李焕德.内源性氢化可的松为探针的CYP3A活性测定.中南药学,2006,4(2)：104-106.
10 Rouits E, Boisdron-Celle M, Morel A, et al. SRouits E, Boisdron-Celle M, Morel A, Gamelin E. Simple and sensitive high-performance liquid chromatography method for simultaneous determination of urinary free cortisol and 6beta-hydroxycortisol in routine practice. For CYP3A4 activity evaluation in basal conditions and after grapefruit juice intake. J Chromatogr B Analyt Technol Biomed Life Sci, 2003,793(2):357-366.
11 Kawaguchi A, Ohmori M, Tsuruoka S, et al. Drug interaction between St John's Wort and quazepam. Br J Clin Pharmacol,2004,58 (4),403-410.
12 Barrett YC, Akinsanya B, Chang SY, et al. Automated on-line SPE LC-MS/MS method to quantitate 6beta-hydroxycortisol and cortisol in human urine:use of the 6beta-hydroxycortisol to cortisol ratio as an indicator of CYP3A4 activity. J Chromatogr B Analyt Technol Biomed Life Sci,2005,821(2):159-165.
13 Furuta T, Mori C, Suzuki A, et al. Simultaneous determination of 6beta-hydroxycortisol and cortisol in human urine by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3 A activity determined by the cortisol 6beta-hydroxylation clearance. J Chromatogr B Analyt Technol Biomed Life Sci,2004,801(2):165-171.
14 Chen YC, Gotzkowsky SK, Nafziger AN, et al. Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br J Clin Pharmacol,2006,62(2):187-195.
15 Wieling J, Tamminga WJ, Sakiman EP, et al. Wieling J, Tamminga WJ, Sakiman EP, Oosterhuis B, Wemer J, Jonkman JH. Evaluation of analytical and clinical performance of a dual-probe phenotyping method for CYP2D6 polymorphism and CYP3A4 activity screening. Ther Drug Monit,2000,22(4):486-496.
16 Kuo BP, Hu OY, Hsiong CH, et al. Single-point plasma or urine dextromethorphan method for determining CYP3A activity [J]. Biopharm Drug Dispos,2003, 24(9):367-373.
17 Kashuba AD, Nafziger AN, Kearns GL, et al. Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity. Pharmacogenetics, 1999,9(4):453-462.
18 Drabant S, Toth M, Bereczki A, et al. Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug alprazolam. Eur J Clin Pharmacol,2006,62(7):587-588.
19 Wennerholm A, Allqvist A, Svensson JO, et al. Alprazolam as a probe for CYP3A using a single blood sample:pharmacokinetics of parent drug, and of alpha-and 4-hydroxy metabolites in healthy subjects. Eur J Clin Pharmacol,2005, 61(2):113-118.
20 [FDA/CDER]Food and Drug Administration/Center for Drug Evaluation and Research (1999) Guidance for industry:in vivo drug metabolism/drug interaction studies:study design, data analysis and recommendations for dosing and labeling. Oct 6,1999. Center for Drug Evaluation and Research, Rockville, MD.
21 Laine K, Ahokoski O, Huupponen R, et al. Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone. Eur J Clin Pharmacol,2003,59(10):761-766.
22 Dresser GK, Wacher V, Wong S, et al. Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo. Clin Pharmacol Ther,2002,72(3),247-255
23 MF Paine, WW Widmer, HL Hart, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutri,2006,83(5):1097-1105
24 Sugimoto K, Ohmori M, Tsuruoka S, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther, 2001,70(6):518-524.
25 Chung E, Nafziger AN, Kazierad DJ, et al. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther,2006, 79(4):350-361.
26 Wanwimolruk S, Paine MF, Pusek SN, et al. Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4? Br J Clin Pharmacol, 2002,54(6):643-651.
27 Paine MF, Wagner DA, Hoffmaster KA, et al. Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin. Clin Pharmacol Ther,2002,72(5):524-535.
28 Bottiger Y. Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4. Eur J Clin Pharmacol,2006,62(8):621-625.
29 Yin OQ, Tomlinson B, Waye MM, et al. Pharmacogenetics and herb-drug interactions:experience with Ginkgo biloba and omeprazole. Pharmacogenetics, 2004,14(12):841-50.
30 Kharasch ED, Russell M, Garton K, et al. Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Anesthesiology,1997,87(1):26-35.
31 Kharasch ED, Walker A, Hoffer C, et al. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity:noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther,2004,76(5):452-466.
32 Lowry JA, Kearns GL, Abdel-Rahman SM, et al. Cisapride:a potential model substrate to assess cytochrome P4503A4 activity in vivo. Clin Pharmacol Ther, 2003,73(3):209-222.
33 Damkier P, Brosen K. Quinidine as a probe for CYP3A4 activity:intrasubject variability and lack of correlation with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Clin Pharmacol Ther,2000,68(2):199-209.
34 Xie HJ, Yasar U, Sandberg M, et al. Paeoniae Radix, a traditional Chinese medicine, and CYP2C9 activity. J Clin Pharm Ther,2002,27 (3):2291
35 Mohutsky MA, Anderson GD, Miller JW, et al. Ginkgo biloba:evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther,2006,13(1):24-31.
36 Greenblatt DJ, von Moltke LL, Luo Y, et al. Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol,2006,46 (2):214-221.
37杨秋慧,孟宪清,李玉兰.复方丹参诱导人体P4501A2作用观察.哈尔滨医科大学学报,1997,31(4)：295-296.
38苗丽娟,孟宪清.刺五加对大鼠及人肝微粒体酶CYP450的作用观察.哈尔滨医科大学学报,1998,32(5)：336-339.
39周权.代谢性药物相互作用.见：曾苏.药物代谢学[M].第一版.杭州：浙江大学出版社,2004.
40 Saruwatari J, Nakagawa K, Shindo J, et al. The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man. J Pharm Pharmacol,200,55(11):1553-1559.
41 Schmider J, Brockmoller J, Arold G, et al. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics, 1999,9(6):725-734.
42 Donovan JL, DeVane CL, Chavin KD, et al. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos,2003,31(5):519-522.
43 Markowitz JS, Donovan JL, Lindsay DeVane C, et al. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol,2003,23(6):576-581.
44 Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos, 2004,32(12):1333-1336.
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