经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点

目的研究经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点,并与外周静脉注射化疗相比较,探讨区域性门静脉灌注化疗的优势。方法 24只Wistar大鼠随机分组后分别经门静脉插管区域灌注及经外周静脉注射5-Fu,剂量均为20 mg/kg。采用高效液相色谱法(HPLC)测定两组给药后5、10、20、30、45、60、90、120、180 min不同时间点血浆和肝脏组织中5-Fu的浓度,对比两组5-Fu在肝脏和血浆中的药动学数据。对比两组的穿透比率、穿透指数及治疗优势度。结果经外周静脉注射5-Fu时,肝脏组织中的药物峰浓度(Cmax)和药物时量曲线下面积(AUC)分别为(13.79±4.56)μg/g及(342.20±108.20)μg·h/ml;血浆中的Cmax和AUC分别为(36.85±5.96)μg/g及(842.00±158.00)μg·h/ml。经门静脉灌注时,肝脏组织中的Cmax和AUC分别为(28.21±4.46)μg/g及(733.60±180.30)μg·h/ml;血浆中的Cmax和AUC分别为(21.02±4.06)μg/g及(529.80±111.50)μg·h/ml。门静脉灌注化疗与外周静脉注射相比的治疗优势度为3.37。结论与外周静脉注射全身化疗比较,区域性门静脉灌注5-Fu化疗可显著提高肝脏组织中的药物时-量作用强度,同时减少化疗药物在外周血中的分布,可作为肝癌化疗有效的给药途径     

大鼠腹腔注射ACNP-MMC的药代动力学

目的:研究新型淋巴靶向制剂纳米活性炭吸附丝裂霉素(ACNP-MMC)腹腔给药的药物代谢动力学特点。方法:采用液-液萃取制备血浆和组织液,利用高效液相色谱法(HPLC)测定MMC和ACNP-MMC腹腔给药后的药物代谢动力学数据。结果:MMC组织浓度线性范围为16～16000ng/mL(r=0.99694),方法回收率为82%～106%,日内日间精密度(RSD%)为1.45%～14.10%,最低检测浓度为5ng/mL。大鼠单次腹腔注射(MMC组,4mg/kg)后,10min时各组织药物浓度达到峰值,2h血液和各组织中药物浓度即降低至检测不出水平。ACNP-MMC组单次腹腔注射后在2h内与MMC组相似,但在2h后药物浓度持续保持在较高水平,在48h仍高于有效抗肿瘤药物浓度(>10μg/L)。MMC和ACNP-MMC组间及其对应的各脏器间差异有统计学意义,P<0.001。结论:纳米活性炭吸附MMC进行腹腔化疗具有在较长时间内维持腹腔组织内MMC的高浓度,同时有降低血中抗癌药物浓度的能力。     

高效液相色谱法检测KB和KBv200细胞裸鼠移植瘤组织中阿霉素浓度

背景与目的:阿霉素是一种应用广泛的抗癌药物,肿瘤组织中阿霉素的浓度比血液浓度能更准确地反映其疗效。本研究采用肿瘤组织中阿霉素浓度的高效液相色谱检测法比较耐药KBv200细胞和敏感KB细胞裸鼠移植瘤组织中阿霉素的浓度。方法:建立KB、KBv200细胞裸鼠移植瘤模型,以高效液相色谱法检测肿瘤组织中阿霉素的浓度。色谱柱为反相BDSC18柱(250mm×4.6mm,ID5μm),流动相:乙腈/0.02mol/L磷酸二氢钾(1∶2.4,V/V,pH3.9);激发波长480nm,发射波长580nm;流速:1.0mL/min。结果:在所建立的色谱条件下,肿瘤组织中阿霉素的线性范围为29.3～7500ng/g,线性相关系数r=0.9998,最低检测浓度为14ng/g。在3750、468.8和117.2ng/g三个浓度的萃取回收率分别为(99.35±7.65)%、(99.79±5.73)%和(103.67±6.76)%,方法回收率分别为(91.89±7.03)%、(94.94±5.18)%、(100.83±5.32)%,日内及日间RSD均小于4.2%。在阿霉素注射后第1、3、5h,KBv200细胞裸鼠移植瘤组织中阿霉素的浓度分别为(139.32±54.68)、(260.00±126.11)和(173.26±13.88)ng/g,KB细胞裸鼠移植瘤组织中分别为(385.13±42.55)、(523.38±138.84)和(460.75±86.85)ng/g,在相同的时间点,KBv200细胞裸鼠移植瘤组织中阿霉素的浓度明显低于其敏感KB细胞株(P<0.05)。结论:采用高效液相色谱法测得耐药细胞肿瘤组织中抗癌药物的浓度低于相应的敏感细胞肿瘤组织。     

注射用紫杉醇脂质体与紫杉醇注射液在肿瘤患者中的药动学比较

目的:建立人血浆中紫杉醇(paclitaxel,PTX)浓度的液相色谱-质谱(liquid chromatography-mass spectometry,LC-MS)检测方法,比较注射用紫杉醇脂质体(paclitaxelliposomeforinjection,L-PTX)和常规紫杉醇注射液(conventional paclitaxel injection,C-PTX)在肿瘤患者中的药动学特征。方法:采用随机、开放和对照的试验设计方案。试验分2组,每组各8例患者,分别静脉滴注175mg/m2L-PTX或C-PTX,并于静脉滴注过程中的1.5和3h及滴注结束后的0.25、0.5、1、2、4、8、12、24、36、48和72h采集受试者血样。LC-MS法测定血药浓度,应用DAS2.0软件计算药动学参数并进行比较。结果:患者单次静脉滴注175mg/m2L-PTX与C-PTX的主要药动学参数:血浆峰浓度(Cmax)分别为6455±2247和7400±1542μg/L;药物血浆浓度-时间曲线下面积(area under the plasma concentration-time curve,AUC0-∞)分别为14812±2846和21693±2657μg·h·L-1;血浆消除半衰期(t1/2z)分别为30.5±7.3和13.7±3.2h;表观分布容积(Vz)分别为526.8±112.1和162.9±49.1L/m2;血浆清除率(plasmaclearance,CLz)分别为12.3±2.7和8.2±1.0L·h-1·m-2。经统计学分析,2组的药动学参数差异有统计学意义(P<0.05)。结论:脂质体包裹后改变了PTX的体内药动学特性,与常规PTX相比,脂质体制剂在肿瘤患者体内的分布特性和消除情况有显著不同,具有更好的组织亲和性与缓释作用。     

肿瘤患者单次和多次口服替吉奥片的药动学研究

目的:评价肿瘤患者单次和多次口服替吉奥片的药动学特征.方法:设单次给药组10例,给药剂量60 mg;连续给药组9例,每次给药剂量60 mg,1日2次,连续服用7 d.采用液相色谱-串联质谱法测定血浆中替加氟及其代谢物5-氟脲嘧啶(5-FU)、吉美嘧啶(CDHP)和奥替拉西(Oxo)的浓度.采用DAS2.0药动学软件进行药动学参数的分析和计算.结果:单次给药替加氟Cmax为(1407±383)ng·mL-1,AUC0-t为(15 403±8439)ng·h·mL-1,活性代谢物5-氟脲嘧啶Cmax为(128±36)ng·mL-1,AUC0-t为(539±138)ng·h·mL-1,吉美嘧啶Cmax为(222±93)ng·mL-1,AUC0-t为(962±390)ng·h·mL-1,奥替拉西Cmax为(33.2±14.6)ng·mL-1,AUC0-t为(117±64)ng·h·mL-1.与单次给药相比,多次给药后替加氟的Cmax和AUC增加明显(P<0.05),但其增加程度与理论蓄积系数接近,而代谢物氟脲嘧啶、吉美嘧啶及奥替拉西的Cmax和AUC无明显增加.受试者在研究期间未出现重度以上不良反应.结论:口服替吉奥片后,受试者耐受良好.多次给药后,替吉奥片主要成分的药代动力学行为没有发生明显变化.     

定量PCR检测肝细胞癌患者血浆循环DNA及其临床意义

背景与目的:血循环DNA是一种新的肿瘤诊断及预后判断的标志物.本研究运用定量PCR技术检测肝细胞癌(hepatocellular carcinoma,HCC)患者血浆循环DNA含量并探讨其诊断价值.方法:收集72例HCC患者术前血浆样本,37例肝良性病变(肝硬化以及慢性肝炎)和41例健康志愿者的血浆样本,纯化血浆循环DNA,采用实时定量PCR技术对血浆DNA水平进行检测.应用接受者操作特性(receiver-operating characteristics,ROC)曲线分析血浆循环DNA在HCC诊断中的价值.结果:HCC中位血浆循环DNA浓度(173 ng/mL)显著高于健康对照(9 ng/mL)和肝良性病变组(46 ng/mL)(P<0.001);其ROC曲线下面积(area under the ROC curve,AUC)分别为0.949和0.874.而HCC血浆DNA浓度也显著高于肝硬化及慢性肝炎患者(P=0.001),AUC为0.703.以18.2 ng/mL作为诊断HCC的临界值,其诊断特异度为90.2%,敏感度达90.3%;与血清AFP联合检测可提高HCC诊断效率,AUC上升至0.974,其诊断特异度和敏感度分别为95.1%和94.4%.伴肝内播散或脉管癌栓HCC患者的血浆DNA浓度(261 ng/mL)明显高于不伴肝内播散灶或脉管痛栓患者(142 ng/mL,P=0.035).结论:定量PCR技术可精确定量血浆循环DNA浓度;血浆DNA分析对于HCC诊断,预测肿瘤转移潜能具有重要价值.     

国产替吉奥片剂在恶性肿瘤患者中的生物等效性研究

  目的  研究国产替吉奥片剂在恶性肿瘤患者体内的生物等效性。  方法  采用多中心、开放、随机、双周期交叉试验设计, 29例恶性肿瘤患者分别口服替吉奥片剂或替吉奥胶囊(S-1), 2个周期间的清洗期为1周。多点采集血样, 采用液相色谱-质谱-质谱联用法测定替加氟、5-氟尿嘧啶(5-FU)、吉美嘧啶(CDHP)和奥替拉西(Oxo)的血药浓度, 采用Phoenix WinNonlin 6.1药动学软件进行药动学参数分析和计算。  结果  受试者口服受试制剂和参比胶囊后, 血浆中替加氟C_max分别为(2 080±601)ng·mL-1和(2 050±615)ng·mL-1, AUC_last分别为(25 300±10 900)ng·h·mL-1和(24 600±11 600)ng·h·mL-1; 5-氟尿嘧啶C_max分别为(161±73.5)ng·mL-1和(166±79.9)ng·mL-1, AUC_last分别为(829±506)ng·h·mL-1和(824±415)ng·h·mL-1; 吉美嘧啶C_max为(351±141)ng·mL-1和(334±143)ng·mL-1, AUC_last(1 570±914)ng·h·mL-1和(1 550±868)ng·h·mL-1; 奥替拉西C_max(68.4±62.4)ng·mL-1和(56.2±39.9)ng·mL-1, AUC_last(243±185)ng·h·mL-1和(241±172)ng·h·mL-1。AUC和C_max经对数转换后进行方差分析及90%置信区间判断, 替吉奥片与S-1胶囊C_max几何均值比的90%置信区间为75%~133%, AUC_last几何均值比的90%置信区间为80%~125%;T_max无显著性差异(P < 0.01)。本试验剂量下替吉奥片剂和S-1胶囊耐受性良好, 无严重不良事件。  结论  替吉奥片剂与S-1胶囊在人体内具有相似的体内过程和药代动力学特征。符合生物等效的相关要求, 可判断替吉奥片剂与S-1胶囊具有生物等效性。      

姜黄素对Raji细胞凋亡及bFGF表达影响的观察

目的:探讨抗血管生成药物姜黄素对人非霍奇金淋巴瘤(NHL)Raji细胞凋亡及碱性成纤维细胞生长因子(bF-GF)表达的影响,为临床抗血管新生治疗NHL提供理论依据。方法:不同浓度(5、10、25和50μmol/L)姜黄素作用Raji细胞不同时间后,倒置相差显微镜下观察Raji细胞形态及生长情况;Annexin V-FITC双标流式细胞术检测姜黄素对细胞凋亡的作用;ELISA检测姜黄素对Raji细胞上清中bFGF含量的影响。结果:显微镜下可见,随姜黄素浓度的增加,Raji细胞由成团生长变为单个散在,细胞数明显减少,细胞体积变小,折光性减弱,有的细胞膜破裂,可见细胞碎片;流式细胞术检测结果显示,作用24、48和72h后10μmol/L姜黄素组细胞凋亡率分别为(11.12±1.05)%、(14.74±0.46)%和(25.11±1.43)%,25μmol/L姜黄素组分别为(25.07±5.40)%、(33.50±5.89)%和(55.98±7.41)%,均高于对照组凋亡率(1.75±0.28)%、(2.25±0.29)%和(2.77±0.61)%,差异有统计学意义,P<0.01。ELISA法检测结果显示,作用24、48和72h对照组上清液中bFGF浓度分别为(643.41±57.12)、(732.26±60.19)和(931.27±81.04)ρg/mL;10μmol/L姜黄素处理组分别为(212.76±20.07)、(173.23±14.76)和(107.21±12.37)ρg/mL;25μmol/L姜黄素处理组分别为(95.32±11.59)、(71.24±10.03)和(36.41±7.58)ρg/mL;Raji细胞经10、25μmol/L姜黄素作用24、48和72h后,bFGF表达水平明显低于对照组,在3个时间点的表达量与对照组相比,差异有统计学意义,P<0.01;不同浓度姜黄素处理组上清液中bFGF含量差异亦有统计学意义,P<0.05。结论:姜黄素对Raji细胞凋亡具有促进作用,能够抑制Raji细胞分泌bFGF,其抑制作用具有浓度、时间依赖性,提示姜黄素可能有抑制血管新生的作用。     

经不同途径区域灌注氟尿嘧啶在肝癌、肝组织及血浆中的浓度差异

背景与目的:肝动脉、肝门静脉灌注区域化疗是肝癌的重要治疗手段,本研究探讨区域性灌注化疗时氟尿嘧啶(fluorouracil,5-FU)在大鼠肝癌和肝脏组织及血浆中的分布,为临床肝脏肿瘤化疗提供参考。方法:将24只荷瘤大鼠随机分为4组,分别经外周静脉(尾静脉)、肝动脉、肝门静脉或结扎肝动脉后经肝门静脉灌注5-FU,剂量为20 mg/kg。采用高效液相色谱法测定肝癌、肝脏组织及血浆中5-FU的含量,并计算药物在血浆、肝脏和肝癌组织间的穿透比率。结果:结扎肝动脉的肝门静脉组5-FU浓度在肝脏和肝癌组织中最高,分别为(22.1±9.5)μg/g和(16.4±7.2)μg/g;其次为肝动脉组;肝门静脉组5-FU浓度在肝癌组织中的浓度较低,为(8.9±3.7)μg/g;外周静脉组5-FU浓度在肝脏和肝癌组织中的药物浓度均为最低,肝癌组织中的浓度仅为(4.3±2.2)μg/g。在血浆中的5-FU浓度正好相反,外周静脉组浓度最高(26.8±12.5)μg/m L,肝动脉组(16.4±9.7)μg/m L、结扎肝动脉的肝门静脉组(15.9±10.1)μg/m L和肝门静脉组(14.9±8.5)μg/m L等3组浓度相近,均明显低于外周静脉组(P<0.05)。5-FU的肝癌/血浆穿透比率依次为结扎肝动脉的肝门静脉组(103.47%),肝动脉组(92.94%),肝门静脉组(59.58%)和外周静脉组(16.08%)。结论:与外周静脉注射全身化疗比较,区域性灌注化疗可显著提高肝癌和肝脏组织中的药物浓度,同时减少化疗药物在外周血中的分布,其中经结扎肝动脉的肝门静脉灌注和经肝动脉灌注是肝癌区域性化疗2种较好的途径。     

CXY-001单次给药和反复给药的毒代动力学研究

背景与目的： 通过CXY-001药物在犬体内的毒代动力学的研究,探讨单次给药及反复给药的药物毒性反应与药物暴露量的相关性。 材料与方法： 分别对Beagle犬经口单次给予不同剂量的CXY-001药物,及反复给予不同剂量的CXY-001药物后,采用液相色谱-质谱-质谱(EC-MS-MS)方法检测犬血清中药物浓度,及观察犬的毒性反应。单次给药试验：给药剂量为227、511、767、1150 mg/kg,每个剂量用1只Beagle犬试验,分别于给药后0.5、1、2、3、4、5、6、8、24 h采血。反复给药试验：给药剂量分别为120、30、 7 mg/kg,连续给药90 d,停药后恢复期观察4周。首次给药后分别于0.5、1、2、3、4、5、6、8、24 h采血;给药中期(第45 d)采血点为药后0.5、5、24 h;末次给药(第90 d)后采血点分别为药后0.5、5、24、48、72和96 h,每组采血动物数为3只。 结果： 单次给药后Beagle犬主要反应为呕吐,227、511、767、1 150 mg/kg 4个剂量组单次给药AUC0-24依次为150 249、263 905、232 640和19 848 ng•h/ml;犬血清中AUCO-∞分别为151 054、 298 069、246 083和117 793 ng•h/ml;Cmax分别为13 400、19 500、29 100和6 910 ng/ml。反复给药120、30、7 mg/kg 3个剂量组首次给药后AUC0-24分别为(123 023±75 308)、(19 246±14 654)和(2 991±996) ng•h/ml,AUC0-∞分别为(200 189±106 688)、(25 145±22 443)和(4 650±1 855) ng•h/ml,Cmax分别为(10 440±5 891)、(3 653±1 776)和 (376±116) ng/ml,第45 d、第90 d相同时间点各组的血药浓度值有一定的波动,药后48 h动物体内血药浓度已低于检测线。仅30 mg/kg剂量组未见毒性作用。 结论： Beagle犬经口给予CXY-001后,在一定剂量范围内(约<600 mg)犬血清中Cmax、AUC0-24和AUC0-∞随着剂量的增加而增加;反复给药于停药后药物清除较快,提示该药连续给药后可能无蓄积作用。     

Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects.

BACKGROUND: Curcumin is a polyphenol, found in the spice turmeric, that has promising anticancer properties, but previous studies suggest that absorption of curcumin may be limited. METHODS: This study examined the pharmacokinetics of a curcumin preparation in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was administered at doses of 10 g (n = 6) and 12 g (n = 6). Subjects were randomly allocated to dose level for a total of six subjects at each dose level. Serum samples were assayed for free curcumin, for its glucuronide, and for its sulfate conjugate. The data were fit to a one-compartment absorption and elimination model. RESULTS: Using a high-performance liquid chromatography assay with a limit of detection of 50 ng/mL, only one subject had detectable free curcumin at any of the 14 time points assayed, but curcumin glucuronides and sulfates were detected in all subjects. Based on the pharmacokinetic model, the area under the curve for the 10 and 12 g doses was estimated (mean +/- SE) to be 35.33 +/- 3.78 and 26.57 +/- 2.97 mug/mL x h, respectively, whereas C(max) was 2.30 +/- 0.26 and 1.73 +/- 0.19 mug/mL. The T(max) and t(1/2) were estimated to be 3.29 +/- 0.43 and 6.77 +/- 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate, not mixed conjugates. CONCLUSION: Curcumin is absorbed after oral dosing in humans and can be detected as glucuronide and sulfate conjugates in plasma.     

盐酸帕洛诺司琼注射液在健康受试者体内的药代动力学研究

  目的  评价盐酸帕洛诺司琼注射液在健康受试者体内的药动学特征。  方法  31例健康受试者分成3组,单次静脉注射盐酸帕洛诺司琼剂量分别为0.125,0.25和0.5 mg。采用超高效液相-串联质谱法（UPLC-MS/MS）测定人血浆中帕洛诺司琼浓度,采用DAS 2.1药动学软件进行药动学参数的分析和计算。  结果  单剂量静脉注射0.125,0.25和0.5 mg的盐酸帕洛诺司琼注射液后,AUC_0~168h分别为（7.5±2.5）、（15.2±4.0）、（34.8±9.7）μg·h·mL-1;消除半衰期t_1/2分别为（27.2±9.5）、（27.2±6.5）、（31.4±5.6）h。AUC_0~168h与剂量呈正相关,相关系数为0.998。受试者在研究期间未发生重度以上不良事件。  结论  本研究建立的检测方法简单、快速、准确、灵敏度高,适合盐酸帕洛诺司琼人体药代动力学研究。单次静脉注射盐酸帕洛诺司琼后,受试者耐受良好。在0.125~0.5 mg剂量范围内,帕洛诺司琼在健康受试者体内表现为线性药动学特征。      

Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.

PURPOSE: To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420. EXPERIMENTAL DESIGN: Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC(0-24)). RESULTS: This patient was assigned to receive erlotinib at a dose level of 70 mg/m(2), but the actual daily dose was 75 mg (78 mg/m(2)). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC(0-24) in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC(0-24) in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and approximately 9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was approximately 130 ng/mL (325 nmol/L). CONCLUSIONS: The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.     

Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study.

PURPOSE: Dactinomycin (actinomycin D) is an antitumor antibiotic used routinely to treat certain pediatric and adult cancers. Despite concerns over the incidence of toxicity, little is known about the pharmacology of dactinomycin. A study was done to investigate dactinomycin pharmacokinetics in children. EXPERIMENTAL DESIGN: Dactinomycin was administered to 31 patients by bolus i.v. infusion, at doses of 0.70 to 1.50 mg/m2. Plasma concentrations were determined by liquid chromatography-mass spectrometry up to 24 hours after drug administration and National Cancer Institute Common Toxicity Criteria was assessed. RESULTS: Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data available to fully characterize this model. A median peak plasma concentration (Cmax) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC0-6), determined in 16 patients with sampling to 6 hours, was 2.67 mg/L.min (range, 1.12-4.90 mg/L.min). After adjusting for body size, AUC0-6 and Cmax were positively related to dose (P = 0.03 and P = 0.04, respectively). Patients who experienced any level of Common Toxicity Criteria grade had a 1.46-fold higher AUC0-6, 95% confidence interval (1.02-2.09). AUC0-6 was higher in patients <40 kg, possibly indicating a greater toxicity risk. CONCLUSIONS: Data presented suggest that dosing of dactinomycin based on surface area is not optimal, either in younger patients in whom the risk of toxicity is greater, or in older patients where doses are capped.     

Pharmacokinetics of 5-FU after S-1 oral administration for adjuvant chemotherapy in gastric cancer patients

We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.     

Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine

Purpose Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemopreventive properties in rodents. It possesses poor systemic availability. We explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin. Methods Male Wistar rats received 340 mg/kg of either unformulated curcumin or curcumin formulated with phosphatidylcholine (Meriva) by oral gavage. Rats were killed at 15, 30, 60 and 120 min post administration. Plasma, intestinal mucosa and liver were analysed for the presence of curcumin and metabolites using HPLC with UV detection. Identity of curcumin and metabolites was verified by negative ion electrospray liquid chromatography/tandem mass spectrometry. Results Curcumin, the accompanying curcuminoids desmethoxycurcumin and bisdesmethoxycurcumin, and the metabolites tetrahydrocurcumin, hexahydrocurcumin, curcumin glucuronide and curcumin sulfate were identified in plasma, intestinal mucosa and liver of rats which had received Meriva. Peak plasma levels and area under the plasma concentration time curve (AUC) values for parent curcumin after administration of Meriva were fivefold higher than the equivalent values seen after unformulated curcumin. Similarly, liver levels of curcumin were higher after administration of Meriva as compared to unformulated curcumin. In contrast, curcumin concentrations in the gastrointestinal mucosa after ingestion of Meriva were somewhat lower than those observed after administration of unformulated curcumin. Similar observations were made for curcumin metabolites as for parent compound. Conclusion The results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin.     

Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.     

姜黄素抑制结肠癌SW480细胞的增殖及其机制

目的:研究姜黄素对人结肠癌SW480细胞增殖以及survivin、caspase-3和p-Akt表达的影响。方法:用不同浓度姜黄素(5～40μmol/L)作用SW480细胞24、48和72 h,MTT法检测姜黄素对SW480细胞生长的抑制作用,Western blotting法检测SW480细胞中survivin、caspase-3和p-Akt蛋白的表达。结果:姜黄素以剂量(5～40μmol/L)和时间(24～72 h)依赖的方式抑制SW480细胞的增殖(P<0.01),40μmol/L姜黄素作用72 h对SW480细胞生长的抑制率可达(75.86±3.93)%。姜黄素抑制SW480细胞中p-Akt、survivin蛋白的表达、促进caspase-3蛋白的表达,均呈时间和剂量依赖性;40μmol/L姜黄素作用SW480细胞48 h后p-Akt和survivin蛋白表达显著减少[(0.204±0.025)vs(0.367±0.035),P<0.01;(0.208±0.014)vs(0.385±0.034),P<0.01],caspase-3蛋白表达显著增加[(0.371±0.028)vs(0.127±0.023),P<0.01]。结论:姜黄素抑制SW480细胞增殖,其机制可能与抑制Akt磷酸化、下调survivin和上调caspase-3蛋白的表达有关。