西替伪麻缓释片在中国志愿者体内的药代动力学研究

目的 研究中国健康志愿者口服西替伪麻缓释片的药动学过程.方法 将24名志愿者随机均分为高剂量组和中剂量组,分别单次口服西替伪麻缓释片1片和2片;单次给药结束1周后,中剂量组12名受试者连续5 d每天口服2片,采用液相色谱-串联质谱法同时测定人血浆中西替利嗪和伪麻黄碱的质量浓度.结果 西替利嗪单次给药后高剂量组和中剂量组的血药峰浓度(Cmax)分别为(134.5±22.0)μg/L和(290.9±47.4)μg/L,0～36 h药时曲线下面积(AUC0-36h)分别为(1 369.3.4±314.9)μg·h/L和(2 403.0±304.9)μ·h/L;伪麻黄碱单次给药后高剂量组和中剂量组的Cmax分别为(434.2±95.0)μg/L和(932.5±280.8)μg/L,AUC0-36 h分别为(6 160.7±1 477.4)μg·h/L和(1 2871.4±4 863.2)μg·h/L.多次给药达稳态后的平均稳态血药浓度(Cav)分别为(135.6±23.4)μg/L和(417.9 4±126.0)μg/L,达峰时间(Tmax)分别为(0.9 4±0.5)h和(4.1 4±1.7)h,AUCss分别为(1 626.7 4±280.8)μg·h/L和(5 015.0±1 511.8)μg·h/L,波动度(DF)分别为1.3±0.2和0.7±0.2,蓄积系数(R)分别为1.3 4±0.1和1.2 4±0.1.结论 所建立的液相色谱-串联质谱法测定方法快速、灵敏、准确、简便;盐酸伪麻黄碱具有缓释特征,多次给药后在体内无蓄积现象.     

丁苯酞及其代谢物在中国健康人体的药代动力学

目的 评价丁苯酞软胶囊在中国健康人体的药代动力学.方法 12名中国健康受试者单次空腹口服丁苯酞软胶囊200 mg,用液相色谱-串联质谱法测定血浆样本中丁苯酞(NBP)和丁苯酞代谢物1(NBP-M1)的浓度;用Phoenix WinNolin计算药代动力学参数.结果 NBP和NBP-M1的主要药代动力学参数,t1/2分别为(10.35 ±0.79),(3.69±0.93)h;tmax分别为(1.23±0.73),(1.90±0.76)h;Cmax分别为(196.95±165.2),(1174.29±322.33) ng·mL-1;AUCo-t分别为(360.92±342.8),(5918.10±1627.51)h·ng·mL-1;CL/F分别为(977.03±664.06),(35.82±10.39) L·h-1.结论 丁苯酞口服吸收迅速,除原型物外,体内还可检测出较大浓度的代谢物.     

异硫氰酸基雷公藤内酯醇活性代谢物雷公藤甲素在大鼠体内的药代动力学

目的观察大鼠单剂量静脉注射异硫氰酸基雷公藤内酯醇后雷公藤甲素的药代动力学。方法将大鼠分为2组(每组5只),分别单次尾静脉注射异硫氰酸基雷公藤内酯醇低、高剂量(4.25,8.50 mg·kg-1)。用LC-MS/MS法,检测大鼠血浆中雷公藤甲素的浓度,用BAPP 3.2软件计算药代动力学参数。结果低、高剂量的主要药代动力学参数如下:Cmax分别为(12.36±1.09),(55.74±21.20)ng·mL-1,Tmax均为(2.0±0.0)min,t1/2分别为(12.82±2.41),(13.73±2.84)h,AUC0-t分别为(245.93±42.50),(1034.45±471.76)ng·min.mL-1。结论在4.25～8.50 mg·kg-1,雷公藤甲素的药代动力学表现出非线性消除特征。     

9-硝基喜树碱犬体内药代动力学研究

目的:研究9硝基喜树碱在犬体内药动学规律。方法:犬静注或灌服3个剂量9硝基喜树碱,血浆9硝基喜树碱浓度用高效液相色谱法及液相质谱联用法检测,浓度时间数据用3P97药代动力学软件进行分析,计算药动学参数,分析AUC、Cmax及ke与剂量的线性关系。结果:犬静注0.5、1、2mg·kg-19硝基喜树碱,t12分别为2.2±2.2、1.8±1.7和0.8±0.6h;AUC0-t分别为105±71、272±81和396±93ng·h·ml-1;犬灌胃1、2、4mg·kg-19硝基喜树碱,Cmax分别为9.3±8.2、42.2±35.7和63.6±5.9ng·ml-1,Tmax分别为0.3±0.1、0.2±0.1、0.4±0.1h,t12分别为1.9±1.3、1.0±0.6和2.8±1.5h,AUC0-t分别为8.9±7.2、16.3±12.3和59.5±25.5ng·h·ml-1;各剂量组t12及ke与剂量无关(P>0.05);口服生物利用度<6%。结论:静脉及灌胃给药后,9硝基喜树碱在犬体内的动力学过程符合二室模型,在本实验所用的剂量范围内为线性动力学过程。9硝基喜树碱灌胃给药后吸收迅速,口服生物利用度低。     

维胺酸大鼠体内的药代动力学

用高效液相色谱法测定了维胺酸在在鼠体内的吸收，分布，排泄，生物利用度及蛋白结合率等药代动力学特性，ＲⅡ３０ｍｇ．ｋｇ＾－１ｉｖ，血清中药物浓度经两次加权的二室模型拟合，Ｔ１／２β为２０．７１ｈ，ＣＬｓ为０．３４Ｌ．ｋｇ＾－１，Ｖｃ为０．９９Ｌ．ｋｇ＾－１ＲⅡ１００及２００ｍｇ．ｋｇ＾－１ｐｏ，经一室开放模型拟合，Ｔ１／２ｋｅ分别１１．９２及１３．０１，ＣＬｓ为０．８７及０．７７Ｌ．ｋｇ＾－１ＰＯ．     

液相色谱-串联质谱法测定大鼠血浆中forsklin的浓度及其药代动力学（英文）

目的建立了测定大鼠血浆中forsklin的液相色谱-串联质谱法（LC-MS/MS）。方法血浆样品经叔丁基甲醚萃取后,以水（0.1%甲酸）-乙腈为流动相梯度洗脱,BetaBasic-C18柱分离。通过电喷雾离子化四极杆串联质谱,以多反应监测（MRM）方式进行正离子检测,用于定量分析的离子对分别为m/z 411→375.3（forsklin）和285→193（地西泮）。结果在本实验条件下,forsklin血浆浓度测定方法的线性范围为0.5~1000 ng/ml,定量下限为0.5 ng/ml。日内、日间精密度（相对标准差RSD）均小于14.4%;准确度（相对误差RE）在-3.5%和3.8%之间。方法的专属性,绝对回收率,稳定性和基质效应均符合要求。结论该法快速、灵敏、准确,可用于forsklin的药代动力学研究。     

沙丁胺醇在家犬体内药代动力学研究

沙丁胺醇（ｓａｌｂｕｔａｍｏｌ）为选择性β－受体激动剂,能选择性激动支气管平滑肌的β２受体,有较强的支气管扩张作用,临床用于治疗支气管哮喘症,该药不易被破坏,故本品口服有效［１］。但因其血药浓度很低,难以实现临床血药浓度监测,因此国内较详细的药代动力学研究报道甚少。 沙丁胺醇体内药物分析方法,国外有文献报道采用气－质联用法（ＧＧＭＳ）［２］,由于仪器及试剂条件限制,该法在许多实验室难以开展。我们采用Ｓｅｐ－Ｐａｋ Ｃ１８固相色谱预处理小柱分离富集后,以反相ＨＰＬＣ荧光法定量检测血浆中沙丁胺醇的分析…     

沙丁胺醇在家兔体内的时间药代动力学

沙丁胺醇（Ｓａｌ）抗哮喘作用的昼夜节律，可能与其在体内的药代动力学的昼夜差别有关。为此本文给家兔灌胃２ｍｇ·ｋｇ－１Ｓａｌ，用ＨＰＬＣ荧光检测１０：００ｈ和２２：００ｈ两个时间动物体内血药浓度。结果表明，Ｓａｌ的药动学参数存在明显的昼夜差别。Ｔｐ白天为（２．２８±０．２０）ｈ，夜间为（１．２５±０．３０）ｈ（Ｐ＜０．０５）；ＡＵＣ白天为（０．４１±０．０９）ｍｍｏｌ／Ｌ·ｈ，夜间为（０．３０±０．０５）ｍｍｏｌ／Ｌ·ｈ（Ｐ＜０．０５）；Ｔ１／２白天是（２．７２±０．２２）ｈ，夜间为（１．８６±０．１３）ｈ（Ｐ＜０．０５）；Ｃｍａｘ昼夜无差别。     

阿莫达非尼片在健康受试者体内的药代动力学研究北大核心CSCD

目的研究单剂量口服阿莫达非尼片在中国健康受试者体内的药代动力学和安全性。方法用单中心、随机、开放、三剂量、三周期自身交叉的试验设计,筛选12例健康受试者并随机分组,分别接受单剂量空腹口服阿莫达非尼片100,200,400 mg。用LC-MS/MS法测定血浆中药物浓度,药代动力学参数用DAS 2.1.1软件。结果阿莫达非尼片100,200,400 mg剂量组的主要药代动力学参数如下:t1/2分别为(11.96±1.37),(12.66±1.56),(13.13±1.05)h,tmax分别为(2.41±1.43),(2.50±1.28),(3.00±1.37)h,Cmax分别为(3117±715.80),(5952±1183),(11522±2821)μg·L^(-1)。AUC0-t分别为(535.49±126.21)×10~2,(1081.53±241.91)×10~2,(2268.71±564.30)×10~2h·μg·L^(-1),AUC0-∞分别为(553.66±124.27)×10~2,(1105.26±250.90)×102,(2293.59±565.52)×10~2h·μg·L^(-1)。结论口服阿莫达非尼100~400 mg在人体内的药代动力学过程符合线性药代动力学特征。12例受试者服药后较安全。     

VND3207及其代谢产物在大鼠体内的药代动力学

目的建立液质联用(HPLC-MS/MS)方法,同时测定血浆中VND3207及其代谢产物的浓度并探讨VND3207在大鼠体内的药代动力学。方法 SD大鼠ig给予VND3207 70 mg.kg-1后,于不同时间点采集血样,血浆样品经C18反相液相色谱柱梯度洗脱,采用串联质谱正离子检测多反应监测模式对VND3207及其代谢产物丁香酸和丁香醇进行定量分析,计算VND3207及其代谢产物的药代动力学参数。结果 VND3207、丁香酸和丁香醇的定量线性范围均为2～2000μg.L-1,最低定量下限为2μg.L-1,日内和日间精密度CV均<15%,准确度为91.2%～110.7%。通过测定SD大鼠ig给予VND3207 70 mg.kg-1后12 h的血药浓度,计算VND3207,丁香酸和丁香醇药时曲线下面积(AUC0-∞)分别为19.37±10.56,1825.32±719.97和(9.89±1.75)mg.L-1.min;消除半衰期(T1/2)分别为78.0±44.6,114.4±17.9和(66.0±23.8)min。结论 建立了快速、灵敏、准确地同时定量大鼠血浆中VND3207,丁香酸和丁香醇液质联用分析方法。VND3207被大鼠快速吸收,其中大量VND3207被氧化为丁香酸,少量被还原为丁香醇。     

重组巴曲酶在猕猴体内的药动学

目的:研究重组巴曲酶(rBAT)在猕猴体内的药动学。方法:用Iodogen法制备125I-rBAT,然后采用交叉试验设计,分别给猕猴静脉注射不同剂量和肌内注射125I-rBAT,用酸沉淀法测定血清125I-rBAT浓度,计算药动学参数。结果:猕猴单次静脉注射0.1,0.4和1.6μg.kg-1的125I-rBAT后,末端半衰期t1/2分别为(1.9±0.8),(2.5±0.5)和(2.3±0.4)h,AUC0~12 h分别为(4.1±1.4),(17.3±3.8)和(63.3±16.6)ng.h.mL-1。肌内注射0.4mg.kg-1的125I-rBAT后,AUC0~12 h为(3.6±0.4)ng.h.mL-1,t1/2为(3.2±0.9)h,Tm ax为(3.3±0.6)h,Cm ax为(0.7±0.1)ng.mL-1,肌内注射的AUC0~12 h显著低于同剂量静脉注射的AUC0~12 h,肌内注射的生物利用度为(20.8±2.3)%。结论:重组巴曲酶在猕猴体内的药动学过程符合线性药动学。     

HPLC-MS法测定犬血浆中三七皂苷R1的血药浓度及其药代动力学

目的:建立用于测定三七皂苷R1血药浓度的液相色谱-质谱联用分析方法,并研究三七皂苷R1在犬体内的药代动力学。方法:Beagle犬6只iv0.7131 mg.kg-1三七皂苷R1后采集系列血样,利用LC-MS联用系统测定血浆药物浓度,并用3P97软件拟合求算药代动力学参数。结果:三七皂苷R1浓度在5.0~2 000μg.L-1内,线性关系良好(γ=0.9996)。绝对回收率高于90%,日内、日间RSD均小于15%,符合生物样品分析要求。6只Beagle犬iv 0.7131 mg.kg-1三七皂苷R1后的血药浓度-时间曲线符合二室模型,其分布和消除相的半衰期分别为38.59 min和230.06 min。曲线下面积(AUC)、中央室分布容积(V)和血浆清除率(CL)分别为67353.75 mg.min.ml-1,3.53 L.kg-1和0.1068L.kg-1.min-1。结论:建立的LC-MS联用方法专属性强,灵敏度高,可用于三七皂苷R1的体内定量分析。     

Pharmacokinetics of panaxatrol disuccinate sodium, a novel anti-cancer drug from Panax notoginseng, in healthy volunteers and patients with advanced solid tumors

Aim:

To evaluate single-dose and multiple-dose pharmacokinetics of panaxatrol disuccinate sodium in healthy volunteers and patients with advanced solid tumors.

Methods:

In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m⁻²). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m⁻² daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system — Drug and Statistics (DAS) — was applied to assess plasma panaxatrol disuccinate sodium concentration-time data.

Results:

After a single intravenous dose of 70, 100, or 140 mg·m⁻² was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC_0–t, MRT_0–t, VRT_0–t, t_1/2Z, CL_z/F, V_z/F, and C₀ (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (C_max), trough concentration (C_min), average concentration (C_av), mean steady state AUC (AUC_ss) and the degree of fluctuation were 13.96±15.48 mg·L⁻¹, 0.18±0.29 mg·L⁻¹, 0.15±0.29 mg·L⁻¹, 3.58±6.94 mg·L⁻¹·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious.

Conclusion:

The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m⁻² panaxatrol disuccinate sodium in the 30-day continuous intravenous injection. All subjects were evaluated for tolerability throughout the study. Thus, the phase II dose of panaxatrol disuccinate sodium may be considered to be 100 mg·m⁻² for a 30-day continuous intravenous injection to treat patients with advanced solid tumors.     

高效液相质谱联用法测定人血浆中蒿甲醚及其活性代谢物双氢青蒿素的浓度

目的建立高效液相质谱联用法以测定人血浆中蒿甲醚(ARM)及其活性代谢物双氢青蒿素(DHA)的浓度.方法色谱条件色谱柱为C18(150 mm×4.6 mm,5μm),流动相为0.2%醋酸-甲醇梯度洗脱系统,流速为1.0 mL·min-4.质谱条件大气压化学电离方法(APCI)采集正离子,SIM方式对ARM和DHA检测m/z 221,对内标(青蒿素)检测m/z 283.血浆样品的预处理采用甲基叔丁基醚萃取法.结果ARM和DHA的线性范围为5～300μg·L-1,相关系数r＞0.999 0,检测限均为2μg·L-11.ARM和DHA日内和日间测定的RSD＜9.3%,回收率在92%～105%的范围内,提取回收率为80%～96%.结论该法简便、准确、灵敏、专属,适用于ARM和DHA的人体药动学研究.     

Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys

Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. The concentration-time profiles observed in adult monkeys following oral administration of 100 μg/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.     

Pharmacokinetics of methysergide and its metabolite methylergometrine in man

Summary Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study.The systemic availability of methysergide was only 13%, most probably due to a high degree of first-pass metabolism to methylergometrine. We also found evidence of extrahepatic clearance of methysergide.After oral administration the plasma concentrations of the metabolite were considerably higher than those of the parent drug and the area under the plasma concentration curve (AUC) for methylergometrine was more than ten times greater than for methysergide.Our findings may be relevant to the treatment of migraine if methylergometrine contributes to the effect of methysergide.Methylergometrine had a significantly longer elimination half-life than methysergide (223±43 min vs 62.0±8.3 min and 174±35 min vs 44.8±8.1 min in the oral and intravenous studies respectively).     

Pharmacokinetics of pirprofen and its pyrrol metabolite in elderly patients

Summary Plasma concentrations of pirprofen and of its pyrrol metabolite were assessed in 9 elderly patients (3 males, 6 females; mean age 76 years) suffering from chronic degenerative disease. Pirprofen 400 mg in 4 ml was administered i.m. and the pharmacokinetic profile of the drug and the metabolite was calculated.The AUC, C_max and t_1/2 of pirprofen were similar to those found in previous studies, and, as expected, those parameters for the pyrrol metabolite were lower (C_max=2.8 µg/ml^–1; t_max=6.4 h; AUC(0–32)=56.5 µg · h · ml^–1). One patient (n=8) showed different pharmacokinetic behaviour, which is discussed.The data suggest that age has little influence on the pharmacokinetic of pirprofen, although unpredictable responses should always be considered in clinical practice.     

甲胺及其代谢产物甲醛在动物体内的药代动力学

目的进一步了解血浆氨基脲敏感型胺氧化酶(SSAO)活性与内源性甲醛的生理学与病理学意义。方法采用高效液相色谱法测定小鼠、大鼠和兔血浆中SSAO活性和静脉给予甲胺后甲胺及其代谢产物甲醛浓度。结果小鼠、大鼠和兔血浆中SSAO活性分别为(4.1±1.0),(2.0±0.3)和(325.8±3.9)μmol·h-1·L-1。3种动物单次iv甲胺后,甲胺的分布和代谢迅速。小鼠单次iv4.2mg·kg-1甲胺后甲醛浓度在代谢初期缓慢上升,在20~40min达峰后缓慢消除。而大鼠单次iv4.2mg·kg-1甲胺后血浆甲醛浓度无明显改变。兔单次iv2.3,9.6和36.8mg·kg-1甲胺后,甲胺AUC与剂量不成比例,Cl随剂量增加明显减少,呈非线性动力学特征。甲醛在兔体内消除较快,甲醛AUC与甲胺剂量的比值和全身清除率Cl无明显差异,但ke随给予甲胺剂量的增大而减少,t1/2显著延长。结论甲胺在3种动物间代谢情况相似,其代谢产物甲醛则明显不同。甲胺给予剂量的不同可能导致甲胺代谢动力学的改变,进而可能影响甲醛的代谢。     

反义寡核苷酸药物癌泰得及其代谢产物的猕猴体内药代动力学研究

研究反义寡核苷酸药物癌泰得(cantide)及其代谢产物在猕猴体内的药代动力学特征。通过采用两步固相萃取法结合无胶筛分毛细管电泳技术测定猕猴血浆中的癌泰得及其代谢产物的血药浓度,并计算药代动力学参数。研究比较了猕猴单次静脉滴注不同剂量(8,16,24 mg.kg-1)癌泰得后血浆中原形药物及其代谢产物M1和M2的药代动力学行为。猕猴经静脉滴注给药后,癌泰得在血浆中消除迅速,末端t1/2为57.91～77.97 min,其Cmax、AUC0-inf和AUC0-t与给药剂量的线性相关系数(r)分别为0.991 8、0.956 8和0.977 3。代谢产物紧随原形药物之后达到峰浓度,且峰浓度均明显低于原形药物。原形药物及其代谢产物M1和M2的CLs分别为1.60～2.19、5.92～8.58和6.07～8.78 mL.min-1.kg-1。结果表明癌泰得原形及其代谢产物的Cmax、AUC0-inf和AUC0-t均随给药剂量增加而增加。代谢产物的清除率大于原形药物,且代谢产物在高剂量组表现为MRT明显延长,末端消除相半衰期亦增大。