白芍总苷在佐剂性关节炎大鼠与正常大鼠体内的药动学差异

目的:比较白芍总苷在佐剂性关节炎大鼠与正常大鼠体内药动学参数的差异,为临床合理用药提供参考。方法:采用大鼠右后足垫皮下注射完全弗氏佐剂建立大鼠佐剂性关节炎模型,应用RP-HPLC测定模型大鼠和正常大鼠灌胃给予白芍总苷后不同时间点的芍药苷的血药浓度,运用PKSolver V2.0软件计算药动学参数。结果:高、中、低剂量(1.80,0.90,0.47 g·kg~(-1))给药时,模型组大鼠体内芍药苷的药峰浓度(C_(max))分别为(7.93±1.09),(4.81±1.06),(1.02±0.82)mg·L~(-1),达峰时间(T_(max))均为180 min;在正常大鼠体内,芍药苷的半衰期(t_(1/2))分别为(215.63±5.26),(213.16±4.18),(208.55±4.94)min;C_(max)分别为(52.39±2.49),(24.52±1.69),(5.79±0.52)mg·L~(-1),AUC_(0-t)分别为(12 564.08±467.37),(5 839.10±380.86),(1 439.95±144.39)mg·L~(-1)·min;T_(max)均为150 min。结论:在类风湿性关节炎状态下芍药苷的吸收速率减缓,C_(max),AUC_(0-t)和AUC_(0-∞)均显著减小;类风湿性关节炎能影响白芍总苷在大鼠体内的药动学行为。     

三七总皂苷对杠柳毒苷药代动力学的影响

[目的]建立液相色谱-质谱联用(LC-MS/MS)定量分析方法,考察三七总皂苷对杠柳毒苷在大鼠体内的药动学影响。[方法]将18只大鼠随机分成杠柳毒苷单独给药组、杠柳毒苷和低剂量三七总皂苷配伍组、杠柳毒苷和高剂量三七总皂苷配伍组,大鼠连续口服给药7 d,在最后1次给药前和给药后不同的时间点从眼底静脉丛取血,采用LC-MS/MS法,以补骨脂素为内标,测定大鼠体内杠柳毒苷的含量,并运用DAS 1.0软件计算待测物的药动学参数。[结果]杠柳毒苷在1~500 ng/mL的范围内线性关系良好,方法学符合要求。药动学结果表明,杠柳毒苷配伍三七总皂苷后,杠柳毒苷在大鼠血浆中的主要药动学参数C_(max)、AUC_(0-t)、AUC_(0-∞)与杠柳毒苷单独给药相比存在统计学差异。[结论]本研究所建立的LC-MS/MS方法快速、灵敏、准确,可用于杠柳毒苷在大鼠体内的药动学研究。三七总皂苷对杠柳毒苷在大鼠体内的药动学存在影响。     

人参皂苷Rg3及其代谢产物在大鼠体内药动学研究

目的:建立人参皂苷Rg3和其代谢产物人参皂苷Rh2血浆药物测定方法,探讨它们在大鼠体内药代动力学情况。方法:采用交叉给药设计,应用高效液相色谱法测定Wistar大鼠单次单剂量灌胃人参皂苷Rg3(50 mg/kg)后的血液中人参皂苷Rg3和人参皂苷Rh2的浓度,利用DAS2.0软件计算药动学参数。结果:口服人参皂苷Rg3后,人参皂苷Rg3在大鼠体内药-时曲线呈二室模型,主要药动学参数Cmax(81.55±24.57)mg/L,t1/2(4.27±1.35)min,AUC0-t(219.25±81.38)mg·min/L。人参皂苷Rh2在大鼠体内药-时曲线同样呈二室模型,主要药动学参数Cmax(6.17±1.34)mg/L,t1/2(3.25±0.17)min,AUC0-t(11.48±3.72)mg·min/L。结论:人参皂苷Rg3口服灌胃后,虽然在大鼠体内可以代谢为人参皂苷Rh2,但是人参皂苷Rh2在体内的量远小于人参皂苷Rg3。     

银杏蜜环口服溶液与阿司匹林的药物相互作用研究

目的:考察银杏蜜环口服溶液是否影响抗血小板聚集药物阿司匹林在大鼠体内药代动力学性质,评价合并用药引起的药物相互作用风险。方法:采用LC-MS/MS建立了阿司匹林及主要代谢物水杨酸血药浓度分析方法。实验大鼠分为309 mg/kg和618 mg/kg银杏蜜环口服溶液合并阿司匹林组及阿司匹林单用组。采集第1天和连续给药8天的大鼠药后不同时间点血浆,进行血药浓度分析,考察阿司匹林体内暴露水平和药代参数的变化。结果:阿司匹林给药后主要以代谢物水杨酸形式暴露于大鼠血浆中。单次合并银杏蜜环口服溶液后,随着银杏蜜环口服溶液剂量增加,水杨酸在5 h时间点的血药浓度有下降的趋势,但没有达到统计学显著性。连续给药后,与空白对照组相比,阿司匹林与309 mg/kg、618 mg/kg的银杏蜜环口服溶液合用后,水杨酸的达峰时间、峰浓度都没有改变。水杨酸消除半衰期和曲线下面积虽有下降的趋势,但是没有显著性差异。结论:以上结果表明在治疗剂量下,银杏蜜环口服溶液不会明显改变阿司匹林的血浆暴露水平和药代动力学性质,发生药物相互作用风险较小。     

艾可清颗粒不同给药方式对大鼠高效抗逆转录病毒治疗中齐多夫定药代动力学的影响

目的研究艾可清颗粒不同给药方式对大鼠高效抗逆转录病毒治疗(highly active antiretroviral therapy,HAART)中齐多夫定(zidovudine,AZT)药代动力学的影响。方法将36只大鼠分为3组进行灌胃给药:Ⅰ组采用HAART,即拉米夫定(3TC,31.5 mg/kg)加AZT(31.5 mg/kg)加依非韦伦(EFV,63.0 mg/kg);Ⅱ组在HAART给药同时给予艾可清颗粒(525 mg/kg);Ⅲ组在HAART治疗后间隔120 min后给予等量艾可清颗粒。采用液质联用法分别测定各组大鼠给予HAART前及给药后0.5、1、2、3、4、6、8、10、12h时AZT血药浓度;采用DAS 2.0软件计算药物半衰期(t_(1/2))、达峰浓度时间(T_(max))、药物达峰浓度(C_(max))、从0~t时间内的血药浓度-时间曲线下面积(AUC_(0-t))及药物清除率(plasma clearance rate,CL)等药代动力学参数。结果 AZT的回归方程线性关系良好,精密度、回收率、稳定性都得到确定。Ⅱ组、Ⅲ组血药浓度曲线高于Ⅰ组,3组t_(1/2)、T_(max)、C_(max)、AUC_(0-12h)、AUC_(0-∞)及CL比较,差异无统计学意义(P0.05)。结论艾可清颗粒联合HAART可提高AZT最高血药浓度。     

UPLC-MS/MS测定复方丹参方中丹参酮Ⅱ_A、丹参酚酸B、人参皂苷Rg_1及其在大鼠血浆和脑组织的药代动力学研究

建立大鼠血浆和脑组织中丹参酮Ⅱ_A(TSⅡ_A)、丹酚酸B(SAB)、人参皂苷Rg_1(GRg_1)的UPLC-MS/MS分析方法,并开展药物动力学研究。选用SD大鼠,单剂量灌胃(ig)复方丹参方,采集血液与脑组织样品,采用UPLC-MS/MS测定血浆和脑组织中TSⅡ_A、SAB和GRg_1的浓度,以Phoenix Win Nolin 6.1药动学程序软件对数据进行非房室模型拟合,采用统计矩法计算药动学参数。经方法学考证,3种成分的峰面积与其在血样及脑组织中的浓度线性关系良好(r0.992 2);回收率为58.86%~112.1%,日内、日间RSD≤9.7%,准确度及稳定性均符合体内药物分析的要求。大鼠ig给复方丹参方后的血浆药动参数如下:丹参酮Ⅱ_AT_(max)(1.58±0.081)h,C_(max)(725.4±88.20)μg·L~(-1),AUC_(0-t)(2 101.3±124.85)μg·h·L~(-1),MRT_(0-t)(3.66±0.05)h;丹酚酸B T_(max)(1.29±0.21)h,C_(max)(307.9±46.75)μg·L~(-1),AUC_(0-t)(537.4±88.24)μg·h·L~(-1),MRT_(last)(2.08±0.11)h;人参皂苷Rg_1T_(max)(1.42±0.20)h,C_(max)(460.38±154.60)μg·L~(-1),AUC_(0-t)(383.4±88.16)μg·h·L~(-1),MRT_(last)(1.87±0.046)h。脑组织药动参数如下:丹参酮Ⅱ_AT_(max)(0.75±0.22)h,C_(max)(1.41±0.420)ng·g~(-1),AUC_(0-t)(4.34±2.48)ng·h·g~(-1),MRT_(0-t)(4.00±1.90)h;丹酚酸B T_(max)(1.08±0.20)h,C_(max)(21.09±4.850)ng·g~(-1),AUC_(0-t)(14.83±3.160)ng·h·g~(-1),MRT_(0-t)(0.99±0.08)h;人参皂苷Rg_1T_(max)(0.50±0.16)h,C_(max)(130.96±54.220)ng·g~(-1),AUC_(0-t)(136.24±34.350)ng·h·g~(-1),MRT_(0-t)(2.87±0.33)h。该研究所建立的UPLC-MS/MS方法可用于大鼠血浆及脑组织中丹参酮Ⅱ_A、丹酚酸B、人参皂苷Rg_1中的药动学研究。     

西洋参与花旗泽仁在大鼠血浆中人参皂苷Rb_1的药代动力学比较研究

目的:比较花旗泽仁与西洋参中人参皂苷Rb_1在大鼠血浆中药代动力学特征。方法:建立灵敏、可靠的超高液相色谱质谱联用法研究花旗泽仁与西洋参在大鼠体内药代动力学特征,完善花旗泽仁成药性评价。将SD大鼠随机分为花旗泽仁组与西洋参组,分别灌胃给予花旗泽仁、西洋参水煎液,于给药前及给药后一系列时间点采集血浆样品进行含量测定,并利用DAS软件计算药动学参数。将西洋参组与花旗泽仁组活性成分人参皂苷Rb_1的主要药动学参数进行比较,观察主要药动学参数有无显著性差异。结果:在0.05~10μg/mL浓度间人参皂苷Rb_1在血浆中有良好的线性关系,定量下限为0.05μg/mL,日内与日间差异均10%。花旗泽仁组和西洋参组中活性成分人参皂苷Rb_1在大鼠体内的主要药动学参数分别为:达峰浓度(C_(max))(779.6±70.92)和(608.6±85.67)μg/L;浓度达峰时间(T_(max))2和0.75 h;消除半衰期t_(1/2)(15.58±7.574)和(9.947±4.099)h;药时曲线下面积(AUC_(0-t))(9 937±1 503)和(3 662±301.5)μg/L·h;平均驻留时间(MRT_(0-t))(14.67±0.740 6)和(7.825±0.409 0)h;血浆清除率(CL)(0.196 8±0.041 22)和(0.499 2±0.070 02)L/h/kg。与西洋参组比较花旗泽仁组中人参皂苷Rb_1的C_(max)明显增加(P0.01),AUC_(0-t)显著增大(P0.01),t_(1/2)明显增加(P0.05)及MRT_(0-t)也显著增加(P0.01),CL未出现明显差异(P0.01)。结论:花旗泽仁中活性成分人参皂苷Rb_1的体内吸收与代谢相对缓慢,能维持较高的血药浓度。花旗泽仁的配伍可提高西洋参中活性成分人参皂苷Rb_1的吸收量。     

参附注射液多种成分在不同心力衰竭模型大鼠体内药动学比较研究

目的:探讨参附注射液中五种主要活性成分在急性、慢性心力衰竭两种不同心力衰竭模型大鼠体内药动学规律与差异。方法:SD大鼠分为急性组和慢性组,每组6只,各组均按参附注射液0.8 mL尾静脉注射给药,测定各组大鼠血浆中人参皂苷Rg_1、Re、Rb_1、Rc和Rd的血药浓度,比较药动学参数。结果:慢性组人参皂苷Rg_1和Re的C_(max)、AUC_(last)均明显大于急性组(P0.05),t_(1/2)均明显小于急性组(P0.05);人参皂苷Rc的AUC_(last)明显大于急性组(P0.05),MRT_(last)明显小于急性组(P0.05);人参皂苷Rd的AUC_(last)大于急性组,但差异没有显著性(P0.05),t_(1/2)明显小于急性组(P0.05);人参皂苷Rb_1的C_(max)、AUC_(last)、Vz_F、Cl_F、t_(1/2)、MRT_(last)与急性组相比差异均不显著(P0.05)。结论:参附注射液主要活性成分在两种不同心力衰竭模型大鼠的体内过程有所不同。     

人参总皂苷主要成分大鼠体内药动学研究

目的研究人参总皂苷中9种人参皂苷Rb1、Rb2/Rb3、Rc、Rd、Re、Rf、Rg1和Rh1在大鼠体内的药动学。方法大鼠ig 200 mg/kg人参总皂苷后于不同时间点眼底静脉丛取血。生物样本采用正丁醇液-液萃取,经C18柱,应用梯度洗脱程序进行色谱分离(体积流量0.2 m L/min),应用液质联用(LC-MS)技术检测。结果大鼠ig人参总皂苷后,血浆中可测得6种人参皂苷(Rb1、Rb2/Rb3、Rc、Rd、Re和Rg1),其中二醇型的人参皂苷(Rb1、Rb2/Rb3、Rc和Rd)的体内暴露程度及半衰期显著高于三醇型的人参皂苷(Re和Rg1)。结论建立的人参皂苷血药浓度测定方法简便、灵敏、特异,适用于大鼠血浆中各人参皂苷的测定及人参总皂苷的药动学研究。     

人参皂苷Rb_1在心肌缺血大鼠体内的药动学研究

目的研究人参皂苷Rb_1在正常大鼠和急性心肌缺血模型大鼠体内的药动学。方法以垂体后叶素(PIT)制备急性心肌缺血大鼠模型,实验分3个正常对照组和3个模型组,分别给予高、中、低剂量的人参皂苷Rb_1(400,200,100 mg·kg~(-1)),单次灌胃给药后于不同时点采血,以三七皂苷R_1为内标,采用LC-MS/MS测定各时点血药浓度,并运用PK Solution 2.0软件计算药动学参数;Western Blot法测定大鼠肝脏中药物代谢酶CYP3a2、CYP2c9、CYP2c19、CYP1a1和CYP1a2蛋白表达。结果人参皂苷Rb_1的线性范围为5~10000 ng·mL~(-1),方法的专属性、提取回收率、日间及日内精密度、稳定性符合生物样品处理要求。与正常组比较,模型组大鼠AUC_(0-t)和C_(max)增加,t_(1/2)和T_(max)延长,CL降低(P0.05或P0.01)。与正常组比较,模型组大鼠CYP3a2、CYP2c9、CYP2c19、CYP1a1和CYP1a2代谢酶蛋白表达明显下降(P0.05或P0.01);人参皂苷Rb_1给药后12 h可诱导CYP1a1和CYP1a2表达。结论该方法专属性强、灵敏度高、准确性好,可用于人参皂苷Rb_1的含量测定及药动学研究。     

松萝酸磷脂复合物在大鼠体内的药动学及组织分布研究

目的研究大鼠ig松萝酸磷脂复合物(UAPC)的药动学和组织分布特征。方法建立大鼠血浆和各组织中松萝酸(UA)的HPLC测定方法,大鼠分别单次ig给予UA和UAPC(35.0、17.5、11.7 mg/kg,以UA计)后,测定不同时间点大鼠血浆和各组织中的UA质量浓度,采用药动学程序软件DAS 2.0计算药动学参数。结果与UA相比,UAPC的主要药动学参数:高剂量35.0 mg/kg时C_(max)、AUC_(0~t)显著增大(P0.05),CL显著降低(P0.01),相对生物利用度为177.83%;中剂量17.5 mg/kg时C_(max)、AUC_(0~t)显著增大(P0.05),CL降低明显(P0.05),相对生物利用度为150.27%;低剂量11.7 mg/kg时C_(max)、AUC0~t增大,CL降低,无显著性差异(P0.05),相对生物利用度为109.67%。UAPC的组织分布特征:高剂量35.0mg/kg时在肝、脾、脑组织中分布较高;中剂量17.5 mg/kg时在肺、脑组织中分布较高;低剂量11.7 mg/kg时在肝、肾组织中分布较高。结论将UA制成UAPC后提高了UA的口服生物利用度,改变了其在大鼠某些脏器组织中的分布。     

川芎嗪、阿魏酸和延胡索乙素在模型与正常大鼠体内药动学比较研究

目的探讨川芎、延胡索中主要活性成分在模型与正常大鼠体内药动学规律与差异。方法 SD大鼠分为对照组和子宫内膜异位症模型组,每组8只,各组均按川芎嗪50mg/kg、阿魏酸30mg/kg、延胡索乙素20mg/kg ig给药,采用高效液相色谱法测定各组大鼠血浆中川芎嗪、阿魏酸和延胡索乙素的质量浓度,DAS2.0程序计算药动学参数。结果模型组川芎嗪药时曲线下面积(AUC_(0~t))、达峰浓度(C_(max))、达峰时间(t_(max))、半衰期(t_(1/2))和平均驻留时间(MRT_(0~t))与对照组相比差异均不显著(P0.05);模型组阿魏酸AUC_(0~t)、C_(max)、t_(max)都小于对照组,但差异没有显著性(P0.05),t_(1/2)、MRT_(0~t)显著小于对照组(P0.05);模型组延胡索乙素AUC_(0~t)、t_(max)、MRT_(0~t)均显著大于对照组(P0.05)。结论川芎、延胡索主要活性成分在正常大鼠和模型大鼠的体内过程有所不同。阿魏酸在模型大鼠体内消除更快,延胡索乙素在模型大鼠体内吸收浓度更高、消除更慢,川芎嗪在正常及模型大鼠的体内过程无显著性差异。     

Effects of Silymarin,Glycyrrhizin, and Oxymatrine on the Pharmacokinetics of Ribavirin and Its Major Metabolite in Rats

The herb‐derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (PO) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, PO), glycyrrhizin (15 mg/kg, intraperitoneal [IP]), or oxymatrine (60 mg/kg, PO). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration‐time curve (AUC_0–t) and the peak plasma concentration (C_max) of ribavirin and ribavirin base by 31.2–44.5% and 48.9–50.0%, respectively. Glycyrrhizin significantly decreased the C_max and AUC_0–t of both ribavirin and its metabolite by 35.3–37.6% and 38.6–39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and C_max. Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the C_max (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine. Copyright © 2016 John Wiley & Sons, Ltd.     

DBS法与传统采样法用于人体药物代谢动力学试验的比较研究

[目的]探讨干血点采样(DBS)法在热毒宁注射液药物代谢动力学试验中的应用,并与传统的血浆采集方法结果进行比较。[方法]从志愿者肘静脉取血,一部分进行LC-MS/MS定量分析,剩余全血分离血浆,进行栀子苷、山栀苷以及京尼平龙胆双糖苷的血药浓度分析。色谱柱Ecosil C18(150 mm×4.6 mm,5μm),流动相甲醇,20 mmol/L甲酸铵,0.1%甲酸,10%甲醇,流速0.5 m L/min,进样量10μL。质谱检测采用ESI离子源,MRM正离子检测模式,质谱运行采集时间11 min。[结果]单次静脉滴注热毒宁注射液,DBS法测定3种栀子成分全血浓度经血细胞比容校正后,栀子苷、山栀苷、京尼平龙胆双糖苷的达峰时间(Tmax)分别为1.41、1.47、1.47 h。峰浓度(Cmax)分别为4.580、0.285、0.550μg/m L。浓度-时间曲线下的面积(AUC0-t)分别为9.060、0.638、1.200(μg·h)/m L。平均驻留时间(MRT0-t)分别为1.52、1.49、1.45 h。[结论]山栀苷、京尼平龙胆双糖苷血浆法和DBS法(校正后)计算的血药浓度和药代参数较为一致,表明DBS法在药物稳定性成分的药物代谢动力学研究中可替代传统血浆处理方法。     

救必应总三萜主要成分在正常和高脂血症大鼠体内的药动学比较

目的比较救必应总三萜主要成分在正常和高脂血症大鼠体内的药动学行为。方法 SD大鼠随机分为正常组和模型组,模型组制备高脂血症大鼠模型,各组单次ig救必应总三萜后于不同时间点取血。采用超高效液相色谱串联质谱(UPLC-MS/MS)测定大鼠血浆中冬青苷O、oblonganoside I、rotundinoside C、ilexside II、长梗冬青苷、苦丁冬青苷H、毛冬青皂苷A_1、竹节参皂苷IVa、救必应酸、rotundanonic acid、冬青素A的浓度,将血药浓度和时间数据导入DAS 2.0软件中以非房室模型拟合药动学参数。结果苷元的吸收速度显著高于三萜皂苷,皂苷含糖的数目越多吸收入血的速度越慢。救必应酸在正常和高脂血症大鼠体内的达峰浓度(C_(max))分别为3 257.9、2 173.8 nmol/L,药-时曲线下面积(AUC_(0～t))分别为29 897.6、24 501.3 nmol·h/L,远超其他10个成分的总和。与正常组相比,模型组大部分成分的达峰时间(t_(max))延长,C_(max)、AUC_(0～t)降低。结论救必应总三萜主要成分在正常和高脂血症大鼠体内的药动学行为存在显著差异,救必应酸为口服总三萜后大鼠体内的主要暴露成分。     

Pharmacokinetic and pharmacodynamic interaction of Danshen-Gegen extract with warfarin and aspirin

Ethnopharmacological relevance

Danshen–Gegen (DG) product has clinically been proven to be an effective agent for heart-tonic efficacy by our previous research. In the mean time, herb–drug interactions between DG product and its commonly co-administered drugs, such as aspirin or warfarin need to be explored to ensure its safe clinical usage.

Aim of the study

Current study aims to investigate whether DG extract interacts with warfarin or aspirin when administered concomitantly to ensure the safety and efficacy of their usage.

Material and methods

Five groups of SD rats (n=6/group) received DG alone (0.15 g/kg, human relevant dose), warfarin alone (0.2 mg/kg), warfarin (0.2 mg/kg) in combination with DG (0.15 g/kg), aspirin alone (10.3 mg/kg), or aspirin (10.3 mg/kg) in combination with DG (0.15 g/kg), respectively. DG product was given twice daily for 5 day. Warfain or aspirin were given once daily for 5 day. DG morning doses were given 2 h post that of warfarin/aspirin. Following first dosing on day 5, plasma samples were collected at different time points. For the pharmacodynamic measurement, whole blood was collected at 30 min after DG dosing or at 2.5 h after warfarin/aspirin dosing, and the prothrombin time assay was conducted.

Results

Co-administration of DG with warfarin could significantly decrease the C_max, AUC and the prothrombin time of warfarin (p<0.05). In the mean time, the C_max and AUC of danshensu, the active bioavailable component of DG were significantly increased (p<0.01) in presence of warfarin. Co-administration of DG with aspirin could significantly increase the C_max and AUC of both aspirin (p<0.01) and its metabolite salicylic acid (p<0.01) and significantly decrease the prothrombin time of aspirin (p<0.05). However, the pharmacokinetics parameters of danshensu were not significantly affected by aspirin.

Conclusion

Our animal study indicated that co-administration of DG with warfarin/aspirin can cause significant pharmacokinetic and pharmacodynamic herb–drug interactions in rat.     

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the C_max and the AUC_0–∞ of clopidogrel in a dose‐dependent manner. As expected, pretreatment of high dose GBE significantly increased the C_max and AUC_0–∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb–drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.     

葛根素自微乳在大鼠体内药代动力学分析

目的:考察葛根素自微乳在大鼠体内的血药浓度经时过程,评价葛根素自微乳的药代动力学及相对生物利用度。方法:单剂量给予大鼠葛根素自微乳和葛根素混悬液,采用HPLC测定血浆中葛根素质量浓度,检测波长250 nm,流动相甲醇(A)-0.1%磷酸水溶液(B)梯度洗脱(0~30 min,20%~25%A;30~40 min,25%~40%A;40~50 min,40%A),运用DAS2.1.1程序拟合药物浓度-时间曲线,计算药代动力学参数及生物利用度。结果:葛根素自微乳和混悬液的tmax分别为0.71,1.1 h,Cmax分别为2.052,1.120 mg·L-1,AUC0-24 h依次为2.901,2.013 mg·h·L-1,葛根素自微乳相对于混悬液的生物利用度144.11%。结论:与葛根素混悬液相比,葛根素自微乳能显著提高葛根素在大鼠体内的生物利用度。     

Influence of rifampicin on the pharmacokinetics of salvianolic acid B may involve inhibition of organic anion transporting polypeptide (Oatp) mediated influx

This article studied the possible effect of rifampicin (RIF), an inhibitor of organic anion transporting polypeptide (Oatp), on the pharmacokinetics of salvianolic acid B (SAB) in rats. Rifampicin was administered intravenously 15 min prior to SAB (5 mg/kg) in rats at doses of 0, 5.0, 10.0 and 20.0 mg/kg, respectively. The concentrations of SAB in plasma and bile were determined using a Shimadzu HPLC system coupled to a LC‐MS‐2010EV mass spectrometer. Compared with the control group, the AUC_0‐t and C_max values of SAB were increased significantly, while the CL_total and CL_bile were decreased significantly. These results suggested that pretreatment with rifampicin prior to SAB administration could decrease significantly the total and bile elimination of SAB and alter its pharmacokinetic profiles. The influence of rifampicin on the pharmacokinetics of SAB may be attributed to the inhibition of Oatp‐mediated influx. Copyright © 2011 John Wiley & Sons, Ltd.     

Quercetin reduced the formation of N‐acetyl‐p‐benzoquinoneimine,a toxic metabolite of paracetamol in rats and isolated rat hepatocytes

N‐acetyl‐p‐benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration–time curve (AUC_0‐∞) and the peakplasma concentration (C_max) of paracetamol were dose‐dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC_0‐∞ and C_max of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1‐mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.