HPLC-MS/MS测定大鼠血浆中刺五加、贯叶连翘提取物主要活性成分浓度及其药动学研究

目的 建立HPLC-MS/MS测定刺五加提取物、贯叶连翘提取物主要活性成分在大鼠血浆中药物浓度的方法,应用于刺五加提取物、贯叶连翘提取物及其联用时主要活性成分在大鼠体内的药动学研究,并使用DAS 3.2.8软件对主要活性成分的药动学参数进行非房室模型拟合。方法 以Welch Ultimate XB-C₁₈(2.1 mm ×100 mm,4.6 μm)为色谱柱,乙腈(含0.1%甲酸)-0.1%甲酸水溶液(含5 mmol·L^-1乙酸铵)为流动相,以300 μL·min^-1的流速进行梯度洗脱,采用电喷雾离子源进行正负离子同时扫描,多反应监测模式进行监测。结果 所建立的方法精密度、准确度良好,提取回收率基本符合生物样品分析方法要求。结论 药动学结果表明,相比于单独给药,联合用药后刺五加苷E t_max缩短,金丝桃素ρ_max升高、t_1/2延长。该药动学结果表明,刺五加提取物、贯叶连翘提取物联用时,很可能通过增加金丝桃素血药浓度、缩短刺五加苷E的达峰时间,从而在体内产生协同抗抑郁作用。     

大黄素甲醚大鼠体内毒代动力学研究

目的 建立用于血浆中大黄素甲醚及其代谢产物含量测定的超高效三重四级杆质谱联用(UPLC-QTOF-MS)方法,研究其原型及代谢产物大鼠体内毒代动力学(TK)行为。方法 开展重复给药毒性试验的首次给药至给药结束的原型及其代谢产物的TK测定,计算动力学参数,评价大鼠口服不同剂量的大黄素甲醚后大鼠血浆中原型及代谢产物的暴露程度。结果 研究发现首末次给药后原型及代谢产物的血浆暴露量与给药剂量无剂量依存关系,3个给药剂量下,大黄素甲醚在体内ρ_max无显著性差异(P>0.05)。大黄素甲醚及其代谢产物在大鼠体内平均驻留时间基本为10 h,并在16 h内消除。随给药剂量增加,代谢产物大黄素-8-O-β-D-葡萄糖苷,芦荟大黄素及大黄素血浆暴露量上升,出现轻度蓄积。结论 大黄素甲醚给药后,原型及其代谢物在体内消除缓慢,因此应严格控制给药剂量和给药间隔,防止体内成分蓄积发生不良反应。     

基于PBPK-TO模型预测CYP3A4调节剂对卡博替尼PK/PD的影响

目的 建立卡博替尼的生理药动学及其主要靶点的靶点占有率联用(PBPK-TO)模型,并预测CYP3A4的调节剂(抑制剂和诱导剂)对其PK/PD的影响。方法 通过运用公式和收集参数,建立卡博替尼的PBPK模型,利用文献实测值进行验证,并联合主要靶点的结合、解离速率常数(k_on、k_off)搭建成PBPK-TO模型;通过结合CYP3A4竞争型抑制剂酮康唑、时间依赖抑制剂地拉韦啶和诱导剂利福平的PBPK模型,研究其对卡博替尼的PK/PD的影响。结果 成功建立了卡博替尼PBPK-TO模型;联合用药时,酮康唑、地拉韦啶和利福平对卡博替尼最大血药浓度(c_max)和激酶靶点的最大靶点占有率(TO_max)均无显著性影响;酮康唑能使卡博替尼血浆药物浓度-时间曲线下面积(AUC_0-t)增加34%,3个主要靶点的靶点占有率大于60%的持续时间(D_TO>60%)均增加30%以上;地拉韦啶能使卡博替尼AUC_0-t增加16%,3个主要靶点的D_{TO >60%}均增加20%以上;利福平能使卡博替尼AUC和靶点的D_{TO >60%}减少70%以上。此外,也研究了联合用药时临床合理的剂量调整方案,当单独使用卡博替尼60 mg作为治疗剂量时,与酮康唑联用剂量需要降低至40 mg;与地拉韦啶联用,不需要调整剂量;与利福平联用时,剂量需要增加到80 mg。结论 建立的PBPK-TO模型能较好地预测CYP3A4抑制剂、诱导剂对卡博替尼PK/PD的影响,为药物相互作用模型研究和临床使用剂量调整提供新思路。     

川芎总酚酸和总生物碱对替莫唑胺在C6胶质瘤大鼠血液和脑及瘤内药动学的影响及机制研究

目的 研究川芎中的总生物碱(TA)、总酚酸(TPA)与替莫唑胺(TMZ)配伍前后对TMZ在C6胶质瘤大鼠血、脑、肿瘤中药动学的影响及相关作用机制。方法 将大鼠C6脑胶质瘤模型随机分为3组,分别单次灌胃给与TMZ、TMZ+TA、TMZ+TPA,于不同时间点处死大鼠取血、脑、肿瘤组织,处理后用液质连用(LC-MS/MS)测定血、脑、肿瘤组织中TMZ含量,统计分析配伍前后药动学参数的差异;另取C6胶质瘤大鼠,分别连续5 d灌胃给与TMZ、TMZ+TA、TMZ+TPA,最后一次给药后处死大鼠取含瘤全脑组织,处理后采用蛋白印迹法测定occludin、claudin-5、ZO-1和caveolin-1蛋白水平。 结果 TMZ分别与TA、TPA配伍后,C6胶质瘤大鼠血中AUC _(0→∞)与TMZ单用组相比无显著变化,t_max、c_max、CL/F发生不同程度的改变。川芎中的TA、TPA均能显著提高TMZ脑内AUC _(0→∞),显著增加脑血分布比,使得TMZ脑靶向性指数DTI_脑分别为1.35、1.24。TMZ与TA、TPA配伍后,C6胶质瘤大鼠肿瘤内主要药动学参数与TMZ单用组相比无显著性差异(P>0.05),TMZ肿瘤靶向性指数DTI_瘤分别为1.07、1.12。与空白对照组相比,川芎TA、TPA均能显著抑制紧密连接蛋白occludin、claudin-5蛋白表达,显著增加caveolin-1蛋白表达,TMZ分别与川芎中的TA、TPA配伍后,可显著增加caveolin-1蛋白表达,显著抑制occludin和claudin-5蛋白表达,但对ZO-1蛋白水平无显著性影响。结论 川芎中的TA、TPA增加TMZ入脑的机制可能与其下调C6胶质瘤大鼠脑内紧密连接蛋白occludin和claudin-5,上调caveolin-1蛋白水平有关。     

盐酸溴己新雾化气溶胶浓度测定及空气动力学粒径分布分析

目的 建立液相色谱-三重四极杆串联质谱法(LC-MS/MS)测定盐酸溴己新雾化气溶胶浓度和分析其粒径分布,并比较注射器采样法及撞击器采样法的差异。方法 采用BEH C₁₈色谱柱(2.1 mm×100 mm,1.7 μm)分离,流动相为体积分数0.1%甲酸水和乙腈,分析时长为2 min,正离子模式下多反应监测测定。同时,对液质联用方法进行了方法学验证,采用该方法对注射器采样法及撞击器采样法采样获得的雾化气溶胶样本进行浓度测定,并基于撞击器采样法计算气溶胶的空气动力学粒径分布。结果 建立的方法专属性、线性、定量限、精密度、准确度、提取回收率和稳定性良好。注射器采样法下总体气溶胶平均药物浓度为17.2 mg·m^-3,撞击器采样法下则为16.8 mg·m^-3。基于撞击器采样法分析得到雾化时间在5 和45 min的气溶胶平均质量中值空气动力学粒径(MMAD)分别为2.21 和2.24 μm,几何标准偏差(GSD)分别为2.76和2.75。结论 本测定方法灵敏度高,精密度好,适用于盐酸溴己新雾化气溶胶浓度测定和粒径分布分析。两种样本采集方式的浓度测定结果基本一致,结果可为吸入制剂雾化气溶胶分析提供参考。     

基于渗透压原理实现尼莫地平可控释药系统的研究

目的 制备基于渗透压原理的尼莫地平渗透泵胶囊,考察影响其释药行为的因素,优化处方并考察其释放机制。方法 根据尼莫地平渗透泵胶囊在体外累积释放度与零级方程拟合度,对囊壳、含药层、助推层的辅料种类和用量进行单因素考察,选出释放主要影响因素为致孔剂用量、含药层并检测其渗透压活性物质用量和膨胀剂用量,利用Box-Behnken设计法对其进一步优化,确定最优处方。制备3批尼莫地平渗透泵胶囊体外释放度与零级方程拟合考察其释药特性,再使用相似因子法(f₂)进行释放机制研究。结果 尼莫地平渗透泵胶囊最优处方为致孔剂(PEG 6000)用量14 mg、含药层渗透压活性物质(NaCl)用量33.7 mg、膨胀剂(PEO 800万)用量33.2 mg,制备的尼莫地平渗透泵胶囊在12 h内药物释放较完全,致孔剂为药物提供释药途径,渗透压活性物质为释药动力。结论 尼莫地平渗透泵胶囊控释效果良好,累积释放度大于90%,并且接近零级释放方程,符合预期。     

双标线性校正法用于一清颗粒的多指标成分定性分析

目的 建立检测清颗粒中8种成分的高效液相色谱法,采用双标线性校正法计算保留时间,考察其准确性和色谱柱的符合率,用于色谱峰定性分析。方法 选用24根不同品牌和型号的C₁₈色谱柱,测定一清颗粒中8种成分的实际保留时间并计算平均值,得到标准保留时间(t_SRT),以峰1表小檗碱和峰8汉黄芩素两个成分作为双标化合物,使用双标线性校正法预测保留时间,并在4根其他品牌和型号的C₁₈色谱柱上进行方法验证。同时,以中间峰盐酸巴马汀为参照物,计算校正因子,用相对保留时间法预测保留时间,比较双标线性校正法和相对保留时间法的优劣。结果 双标线性校正法与相对保留时间法相比,具有更高的保留时间预测正确率和色谱柱符合率,能适用于更多的色谱柱。结论 双标线性校正法能较好地辅助色谱峰定性,在中药多指标成分分析方面有较好的实用价值和应用前景。     

硝唑尼特对骨肉瘤的影响及机制研究

目的 以网络药理学为基础,探讨硝唑尼特(nitazoxanide,NTZ)对骨肉瘤的影响及作用机制。方法 利用化合物靶点预测数据库,筛选NTZ在骨肉瘤治疗中的潜在靶点,构建蛋白互作网络,并在Cytoscape软件中对蛋白互作网络进行可视化分析,通过计算度值,将排名前20的基因视为关键靶基因。借助David数据库对潜在靶点进行富集分析,预测药物潜在作用途径。通过体外实验验证NTZ的抗骨肉瘤的作用,设置NTZ处理组0,10,20,30,40 μmol·L^-1和0.05%DMSO对照组分别作用于骨肉瘤细胞143B细胞,结晶紫、MTT实验检测NTZ对骨肉瘤143B细胞增殖的影响;划痕和Transwell侵袭实验观察迁移侵袭能力;流式细胞术和Hoechst 33258检测细胞凋亡;蛋白印迹法(Western blot)检测细胞蛋白水平的变化。结果 NTZ作用于骨肉瘤的潜在靶点共有78个;Gene Ontology(GO)富集分析涉及306个条目,京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)分析得到80个条目,涉及肿瘤通路、细胞周期信号通路、受体酪氨酸蛋白激酶(ErbB)信号通路等。实验结果表明,NTZ抑制骨肉瘤细胞增殖和迁移侵袭,诱导凋亡,细胞外调节蛋白激酶(ERK1/2)信号通路关键分子ERK1/2的磷酸化显著抑制。结论 NTZ对骨肉瘤的作用涉及多靶点、多过程,能调节ERK1/2信号通路,有效抑制骨肉瘤。     

黏质沙雷氏菌发酵制备舍雷肽酶及基本酶学性质研究

目的 开发微生物发酵生产舍雷肽酶的工艺,并了解基本酶学特性。方法 从家蚕蛹的肠道中分离产酶菌株,单因素实验和响应面实验优化发酵培养基,采用(NH₄)₂SO₄沉淀、超滤和DEAE离子交换层析3步纯化舍雷肽酶,电泳法测定酶的相对分子质量和等电点,考察pH和温度对酶活力和稳定性的影响,并测算酶的反应动力学常数。结果 分离获得一株产舍雷肽酶的黏质沙雷氏菌LL-413菌株,摇瓶发酵产酶活力达到1 126 U·mL^-1,10-L发酵罐中发酵产酶活性达到1 505 U·mL^-1;舍雷肽酶相对分子质量和等电点分别约为52×10³和7.2;酶活最适pH为8.0,在pH 5.0~10.0之间稳定;酶活最适温度为40 ℃,在45 ℃以下稳定。以酪蛋白为底物时,米氏常数(K_m)和最大反应速度(V_max)分别为22.3 mg·mL^-1和1 355 mg·L·min^-1。结论 利用黏质沙雷氏菌LL-413菌株生产舍雷肽酶发酵单位高,酶的蛋白水解能力强、pH和热稳定性好,研究结果为该酶的生产和应用奠定了基础。     

基于分子对接和靶标特异性打分函数的化合物hERG心脏毒性预测

目的 开发基于机器学习的人类快速延迟整流性钾通道基因(the human Etherh-à-go-go-Reloted Gene,hERG)特异性打分函数(RF-hERG-Score),用于预测化合物对hERG的抑制活性(pIC₅₀)。方法 采用随机森林算法,以AutoDock Vina(传统打分函数)分子对接生成的1 847个化合物-hERG复合体结构和实验测定的半抑制浓度(pIC₅₀)数据作为训练集进行训练。结果 在十倍交叉验证中,RF-hERG-Score比RF-Score(通用打分函数)和AutoDock Vina更准确,其预测的pIC₅₀与实验值的皮尔逊相关系数(Rp)为0.603、斯皮尔曼等级相关系数(Rs)为0.623、均方根误差(RMSE)为0.849。在两组外部测试集中,RF-hERG-Score的Rp、Rs和RMSE也高于其他2种方法,并且优于相应文献报道模型的预测性能。结论 RF-hERG-Score提高了hERG抑制剂结合亲和力的预测准确度,为利用计算模拟方法实现药物心脏毒性的较准确预测提供一种新的方案。     

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??OBJECTIVE To establish limited sampling strategies for the estimation of exposure (AUC) to mycophenolic acid (MPA) in patients with autoimmune disease (AID). METHODS The 24 AID patients were treated with MMF 0.75 g q12 h to steady state. Serum MPA concentrations were measured at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 and 12 h after dosage and MPA AUC_{0-12 h} were caculated with the trapezoidal rule. The resulted data were randomly devided into index set and validation set. Multiple liner regression analysis of the index set was used to determine the 1 to 4 sampling estimation models and the models were validated in the validation set. The prediction bias and precision combining clinical feasibility were used to choose the final models. RESULTS The 1-point model based on the simple measurement of c_{12 h} produced acceptable prediction for MPA AUC_{0-12 h}, in which, r² was 0.957, the prediction bias and imprecision were repectively -3.93 and 11.93, both <15%; 4-point model based on 0.5,1.5,6,8 h or 1.5,6,8,12 h sampling times were fitted to MPA AUC_{0-12 h}, with highest correlation coefficients of 0.996, and prediction errors between??15% for 9 patients; other 2 or 3-point models resulted somewhere in-between prediction performance. CONCLUSION Considering the clinical feasibility, the accurate 4-point model AUC=3.19+0.49c_{0.5 h}+1.76c_{1.5 h}+2.95c_{6 h}+5.46c_{8 h} is applicable to MPA AUC monitoring in AID inpatients after morning dose; the simple 1-point model AUC=10.82+13.37c_{12 h} is a good choice for AID outpatients after last-night dose. Bland-Altman analysis reveals that both the two models could effectively predict MPA AUC in Chinese adult AID patients receiving MMF concomitant methylprednisolone therapy     

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??OBJECTIVE To evaluate the bioequivalence of tested and reference torasemide tablets in healthy male volunteers. METHODS A single oral dose of the two formulations was given to 24 healthy male volunteers according to a randomized crossover design. Plasma drug concentrations were determined by HPLC-MS. RESULTS The pharmacokinetic parameters of torasemide of the two preparations were as follows: ??_max (1 408.29??337.27) and (1 487.86??360.24) ng??mL^-1, t_max (0.90??0.42) and (1.03??0.50) h, t_1/2(4.43??0.57) and (4.43??0.60) h, MRT (3.90??0.60) and (4.01??0.72) h, AUC_{0-24 h}(3 886.86??865.99) and (3 906.06??761.72) ng??h??mL^-1, AUC_0-?? (3 936.57??903.93) and (3 956.96??789.98) ng??h??mL^-1, respectively. The relative bioavailability of tested torasemide tablets were (99.8??11.7)% and (99.7??12.0)% when calculated by AUC_{0-24 h} and AUC_0-??, respectively. CONCLUSION The two formulations of torasemide are bioequivalent in healthy Chinese volunteers.     

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??OBJECTIVE To determine the concentrations of low molecular weight heparin (LMWH) in dermal and plasma of rats after administration of LMWH gel to evaluate its pharmacokinetic characteristics. METHODS The rats were treated with abdominal hair removal, followed by administrating LMWH gel. The concentrations of LMWH in the dermal of rats at different time points were measured by microdialysis technique combined with colorimetric method, and the concentrations of LMWH in the blood of rats at different time points were measured by cutting-tail method and Coatest Heparin Kit. RESULTS The LMWH t_max in dermis was 270 min, c_max was (4.40??0.54) IU??mL^-1, t_1/2 was (137.04??87.98) min, AUC_0-t was (911.76??330.69) IU??mL??min^-1, MRT_0-t was (322.67??40.94) min; the LMWH t_max in plasma was 540 min, c_max was (2.23??0.40) IU??mL^-1, t_1/2 was (294.99??183.74) min, AUC_0-t was (110.59??212.41) IU??mL??min, MRT_0-t was (422.48??52.96) min after LMWH gel was percutaneous administrated. CONCLUSION In vivo microdialysis technique combined with colorimetric method can be used for the evaluation of pharmacokinetic characteristics of LMWH gel. The method has the advantages of simple operation with high sensitivity and specificity. LMWH gel have the characteristics of slow transdermal penetration speed and stabilized concentration.
     

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??OBJECTIVE To study the pharmacokinetics and bioequivalence of hydroxysafflor yellow A (HSYA) and hydroxysafflor yellow A nanoemulsion (HYAN) in rats.METHODS Twelve male rats were randomly divided into two groups. The rats were administered intragastrically with HSYA or HYAN, respectively, and then blood was collected from the venous plexus at different time points. HPLC method was used for the determination of HSYA blood concentration.RESULTS The main pharmacokinetic parameters of HYAN were as follows: the area under curve (AUC_{0-24 h}), peak concentration (??_max), peak time (t_max) and clearance (CL) were (31.56??4.58) mg??L??h^-1, (12.75??2.64) mg??L^-1, (0.83??0.54) h and (1.89??0.93) L??h^-1??kg^-1, respectively. The AUC_{0-24 h}, ??_max and t_max of HYAN increased by 5.49, 10.22 and 2.50 times, respectively, and the CL of HYAN was only 1/4 of that of HSYA. The 90% confidence intervals for AUC_{0-24 h} and ??_max were not within the prescribed range of bioequivalence criteria.CONCLUSION Relative to HSYA, the high plasma concentration and prolonged peak time of HYAN in vivo can significantly improve the oral bioavailability of HSYA. HSYA solution and HYAN are not bioequivalent.     

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??OBJECTIVE To investigate the effect of high-fat and high-calorie diets on pharmacokinetics of cefuroxime axetil in healthy Chinese subjects. METHODS A randomized, open-label, single dose and two-way crossover clinical study was conducted. Twelve healthy subjects were randomly divided into two groups, each of which includes six males, then they were given 250 mg of cefuroxime axetil respectively before and after meal. Blood samples were collected at different time points before and after drug administration. The concentration of cefuroxime in plasma was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated by DAS3.2.8 and were analyzed by DAS3.2.8 and SPSS19.0. RESULTS The main pharmacokinetic parameters of fasting and postprandial were as follows: AUC_0-t was (11 402.8??3 556.7) and (18 565.7??2 917.9) ng??h??mL^-1, AUC_0-?? was (11 492.5??3 581.8) and (18 754.7??2 885.6) ng??h??mL^-1, ??_max was (3 406.7??1 188.9) and (5 439.2??1 118.2) ng??mL^-1, t_max was (2.01??0.64) and (2.08??0.79) h, t_1/2 was (1.66??0.38) and (1.60??0.60) h, respectively. The main pharmacokinetic parameters between fasting and high-fat meal groups were analyzed by SPSS19.0 software. There was significant difference in AUC_0-t, AUC_0-?? and ??_max(P<0.01), and no significant difference in t_max and t_1/2 (P>0.05). The ??_max and AUC were increased by 59.7% and 63.2% respectively, t_max is almost unchanged. The equivalence analysis was performed with DAS.3.2.8 software, the 90% confidence intervals for the ratios of AUC_0-t, AUC_0-?? and ??_max for the postprandial/fasting were 137.6%-217.5%, 138.4%-217.3%, 135.4%-207.6%, respectively. None of them fall within the acceptable interval of 80%-125%. CONCLUSION High-fat and high-calorie diets can significantly improve the extent of absorption of cefuroxime axetil in vivo, but does not affect the absorption rate of cefuroxime axetil.     

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??OBJECTIVE To assess the impact of chrysin and naringenin on the pharmacokinetics (PK) of saquinavir (SQV), a substrate of P-glycoprotein (P-gp), in rats. METHODS Fifteen rats were randomized into 3 groups of equal size, and administered orally 30 mg??kg^-1 SQV with or without 40 mg??kg^-1 chrysin or naringenin. The PK of SQV was assessed using non-compartmental analysis and the plasma concentrations of three groups were determined by LC-MS/MS. RESULTS The PK parameters values of SQV, SQV+ naringenin, SQV+ chrysin are as follows:AUC_0-t,882.91,861.32,934.84 ng??h??mL^-1; AUC_0-??,903.97,865.90,947.92 ng??h??mL^-1; ??_max,177.72,89.8,130.72 ng??mL^-1; t_max,1,2,0.5 h;t_1/2,11.73,12.61,13.33 h; MRT_0-??,27.09,31.63,26.60 h; CL/F,21.65,21.45,20.62 mL??kg^-1??h^-1. CONCLUSION Double peak phenomenon is observed in the plasma SQV profiles. Our study demonstrates that chrysin and naringenin can not significantly affect the SQV oral bioavailability and SQV PK profiles in rats.     

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??OBJECTIVE To study the effect of levetiracetam on the absorption of methotrexate in rats and related mechanisms, and provide reference for clinical rational use of two drugs. METHODS ??Pharmacokinetic study: Sprague Dawley (SD) Rats (250??20)g were randomly divided into control group and experimental group, 5 rats in each group, administered by intragastric administration. At the design time point, blood was taken from the fundus venous plexus and centrifuged. Supernatant plasma for detection. ??The intestine experiment was performed in vitro: the rat 10 cm jejunum was taken and the intestinal segment was gently inverted with a capillary tube, and the intestinal anal side was ligated. After the 1 mL KRB buffer was added to the inverted intestinal lumen, the intestinal sac was placed vertically into the drug-containing solution. ??Caco-2 Cells uptake experiments: The Caco-2 cells were inoculated in a 24-well plate for 15 days and then subjected to an uptake experiment. After the incubation for 30 minutes, the cells were stopped for uptake and washed, and the cells were lysed for the detection of methotrexate and protein. Calculate the amount of drug intake. RESULTS ??The main pharmacokinetic parameters of control group and experimental group were as follows: ??_max(ng??mL^-1): 28.6??3.04??54.33??13.97; t_max(min): 50??8.32??70??7.32; AUC_0-t(ng??min??mL^-1): 8 230??2 274?? 15 003??3 359; AUC_0-??(ng??min??mL^-1): 8 450??2 125??15 108??3 371; CL(mL^-1??min??kg^-1): 161.8??27.6?? 90.43??13.76. In the experimental group, the ??_max, t_max, AUC_0-t and AUC_0-?? values of methotrexate increased, and the CL value descreased. The difference was statistically significant. ??Compared with the control group, levetiracetam in the experimental group significantly increased the drug concentration of the methotrexate on the serosal side of the intestine, and its effect was time-dependent. ??Verapamil, digoxin and levetiracetam increased the uptake of methotrexate in the Caco-2 cells, and the effect of levetiracetam was dose-dependent. CONCLUSION When methotrexate and levetiracetam were combined, the drug interactions mediated by the efflux transporter P glycoprotein in the intestinal tract. Methotrexate reduces efflux in the body, increases absorption, and increases plasma concentration. It is suggested that the dose of methotrexate should be adjusted when the combination of methotrexate and levetiracetam, and blood concentration should be monitored if necessary.     

伊潘立酮片在中国健康受试者空腹和餐后条件下的生物等效性研究

目的 研究伊潘立酮片在中国健康受试者空腹和高脂条件下体内的药动学特征并评价生物等效性.方法 采用开放、随机、两周期、两序列自身交叉试验设计,健康受试者分别空腹和餐后口服1 mg伊潘立酮片受试制剂与参比制剂,采集不同时间点的血样.利用液相色谱-质谱联用法检测血浆样品中伊潘立酮及其代谢物羟基伊潘立酮(P88)的浓度,用Ph...     

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??OBJECTIVE To investigate the pharmacokinetics of mycophenolate mofetil in patients with myasthenia gravis, and evaluate the correlation between plasma concentration and AUC. METHODS Eight myasthenia gravis patients older than 18 years old with normal liver and renal function were included in this study. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10 h after the patients were continuously given oral mycophenolate mofetil 2 g??d ^-1for one week. Plasma concentrations of mycophenolate mofetil were determined by HPLC method and data analysis was done by WinNonlin program. RESULTS The main pharmacokinetic parameters of mycophenolate mofetil were as follows??_max was (11.39??3.23) ??g??mL^-1,t_max was (1.5??0.8) h,AUC_{0-12 h} was (38.71??11.23) ??g??h??mL^-1. The ??₂ had the best correlation with AUC (r²=0.80) followed by ??₀ and ??₄ (r²=0.75). CONCLUSION The pharmacokinetics of mycophenolate mofetil has great inter-individual differences, but without significant difference with those in healthy volunteers and transplant patients. The ??₀ can be used for routine therapeutic drug monitoring because of convenience and feasibility.     

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??OBJECTIVE To develop an UPLC method for the determination of mycophenolic acid(MPA) for studying the pharmacokinetics of mycophenolate mofetil(MMF) dispersible tablets after multiple oral doses in early kidney transplant recipients for the rational use in the clinical practice.METHODS A total of 15 Chinese postoperative renal transplant recipients were given a multiple-dose of MMF (750 mg, q12 h) for 6 d. Their blood specimens (2 mL) were collected at 0 and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 h after drug oral administration on day 7. The concentrations of MPA in plasma were determined using UPLC-UV. The main pharmacokinetic parameters were assessed.RESULTS Determination of MPA had good linearity in the concentration range of 0.1-40 ??g??mL^-1, lower limit of quantization was 0.10 ??g??mL^-1.The main pharmacokinetic parameters on day 7 of MMF dispersible tablets were as follows:AUC_{0-12 h} was (24.63??9.51) ??g??h??mL^-1, ??_max was (6.51??3.27) ??g??mL^-1, t_max was (1.83??1.30) h, ??₀ was (1.26??0.99) ??g??mL^-1,CL was (34.66??12.45) L??h^-1. Most of the patients revealed a second small peak in the 4-12 h.CONCLUSION This established method is simple, rapid and suitable for determination of MPA in human plasma.Interindividual variability in AUC_{0-12 h}, ??_max and ??₀ values was considerable in the early renal transplant patients. The MPA exposures under the fixed dose of MMF are low. It is necessary to monitor the MPA-AUC_{0-12 h} to guide the adjustment of drug dosage.