【作者】 易丹；

【导师】 刘世坤；

【作者基本信息】 中南大学 ， 药理学， 2007， 硕士

【摘要】 一、目的研究大豆异黄酮（SIO）在中国健康受试者体内对华法林药动学和药效学的影响以及单独服用大豆异黄酮4周后对常见凝血指标（PT、APTT、TT）的影响,为临床合理用药提供参考。二、方法1.给药方案采用随机、单盲、双周期交叉、安慰剂对照试验设计,洗脱期2周。12名健康受试者（男女各半）按性别各自随机分配到2组,每组6人,分别服用SIO保健品胶囊（含量为75mg）或安慰剂一粒,一日一次（7:00 a.m）,连续5周;第29天在原有给药方案基础上,于8:00 a.m空腹口服单剂量华法林5mg;第二周期两组交叉服用安慰剂或SIO胶囊,其余给药方案不变。2.生物样本采集与保存方法2.1药动学研究血样华法林服药前（0）和服药后0.25,0.5,0.75,1,1.5,2,4,8,12,24,36,48,72,96,120,144h各时刻由肘静脉取血4 mL置肝素化离心管中,立即离心,分离血浆,置-80℃保存待测。2.2药效学研究血样SIO服用前,华法林服药前（0）,服药后4,8,12,24,36,48,72,96,120,144h各时刻由肘静脉取血1.8 mL放于含109 mmol·L^-1枸橼酸钠0.2 mL的抗凝管中,立即离心,分离血浆,置-80℃保存待测。3.生物样本测定方法3.1 HPLC-UV法测定体内华法林的血药浓度。3.2半自动血凝仪测定PT、APTT、TT等凝血指标。三、结果1.SIO对华法林药动学的影响合用SIO后,华法林的药动学参数分别为t_max:1h（0.25-4h）,C_max:730±152 ng·mL^-1,AUC_0→144:27558±2814 ng·h·mL^-1,AUC_0→∞:36403±5550 ng·h·mL^-1,t_1/2:77±28h,CL/F:0.140±0.022 L·h^-1,V/F:15±4L。合用安慰剂后:华法林的药动学参数分别为t_max:0.625h（0.25-2h）,C_max:628±129ng·mL^-1,AUC_0→144:25533±3589 ng·h·mL^-1,AUC_0→∞:29948±3288 ng·h·mL^-1,t_1/2:55±13h,CL/F:0.169±0.019 L·h^-1,V/F:13±4L。合用SIO与合用安慰剂相比:华法林的药动学参数C_max、AUC_0→144、AUC_0→∞、t_1/2显著增加（P＜0.05）;CL/F显著减少（P＜0.05）;t_max和V/F没有显著变化。2.SIO对华法林药效学的影响合用SIO后:华法林的药效学指标分别为PT E_max:13.7±0.6s,PTAUC_0→144:1845±49s·h,APTT E_max:35.5±1.0s,APTT AUC_0→144:4870±164s·h,TT AUC_0→144:1641±100s·h。合用安慰剂后:华法林的药效学指标分别为PT E_max:13.7±0.4s,PT AUC_0→144:1839±52s·h,APTT E_max:35.4±1.2s,APTT AUC_0→144:4860±192s·h,TT AUC_0→144:1640±100s·h。合用SIO与合用安慰剂相比:华法林的药效学参数PT E_max、PTAUC_0→144、APTT E_max、APTT AUC_0→144、TT AUC_0→144没有显著变化。四、结论1.中国健康受试者单独服用SIO 4周后,各凝血指标（PT、APTT、TT）没有显著变化。2.中国健康受试者合用SIO和华法林后,SIO显著增加了华法林的C_max、AUC_0→144、AUC_0→∞。t_1/2,显著减少了华法林的CL/F。3.中国健康受试者合用SIO和华法林后,华法林的药效学指标没有显著变化。更多还原

【Abstract】 OBJECTIVESTo study the effects of SIO on the pharmacokinetics and pharmacodynamics of warfarin,and to assess whether or not soy isoflavone alone has any effect on main blood clotting indexes.METHODS1.Dose administrationA randomized,double-blind,placebo-controlled,two-way cross-over trial was designed.Healthy volunteers（n=12,sex rario=1:1）were randomized to receive either SIO in the first treatment period and placebo in the second treatment period or vice versa.In addition to their randomized trentment,all volunteers received a single dose of 5 mg warfarin on day 29 of each treatment period.2.Blood samples collection2.1 Samples for determination of warfarinSamples were collected before dose of warfarin and at 0.25,0.5,0.75,1, 1.5,2,4,8,12,24,36,48,72,96,120,144h after dose of warfarin,in heparinized centrifuge tubes and then separated by centrifuging and stored at -80℃for detection.2.2 Samples for determination of main blood clotting indexesSamples were collected before dose of SIO,before dose of warfarin and at 4,8,12,24,36,48,72,96,120,144h after dose of warfarin,in vacuum-collected tubes containing sodium citrate solution and then separated by centrifuging and stored at -80℃for detection.3.Sample analysis3.1 Plasma concentration of warfarin was determined by HPLC-UV.3.2 Plasma samples of main blood clotting indexes was determined by semi-automated coagulation analyzer.RESULTS1.The effect of SIO on the Pharmacokinetics of Warfarin Coadministered with SIO,the main Pharmacodynamic parameters of warfarin are as follows:t_max:1h（0.25-4h）,C_max:730±152ng·mL^-1, AUC_0→144:27558±2814ng·h·mL^-1,AUC_0→∞:36403±5550 ng·h·mL^-1,t_1/2: 77±28h,CL/F:0.140±0.022L·h^-1,V/F:15±4L.Coadministered with placebo,the main Pharmacodynamic parameters of warfarin are as follows:t_max:0.625h（0.25-2h）,C_max:628±129ng·mL^-1, AUC_0→144:25533±3589ng·h·mL^-1,AUC_0→∞:29948±3288ng·h·mL^-1,t_1/2: 55±13h,CL/F:0.169±0.019L·h^-1,V/F:13±4L.Coadministered with SIO:C_max、AUC_0→144、AUC_0→∞、t_1/2of warfarin increased（P＜0.05）;CL/F decreased（P＜0.05）;t_maxand V/F showed no statistical change.2.The effect of SIO on the Pharmacodynamics of WarfarinCoadministered with SIO,the main Pharmacokineticic indexes of warfarin are as follows:PT E_max:13.7±0.6s,PT AUC_0→144:1845±49 s·h,APTT E_max:35.5±1.0 s,APTT AUC_0→144:4870±164s·h,TT AUC_0→144:1641±100 s·h.Coadministered with placebo,the main Pharmacokineticic indexes of warfarin are as follows:PT E_max:13.7±0.4 s,PT AUC_0→144:1839±52 s·h,APTT E_max:35.4±1.2 s,APTT AUC_0→144:4860±192 s·h,TT AUC_0→144:1640±100 s·h.Coadministered with SIO:PT E_max、PT AUC_0→144、APTT E_max、APTT AUC_0→144、TT AUC_0→144of warfarin showed no statistical change.CONCLUSIONS1.SIO alone had no effect on these indicators of the clotting process by measurement of PT,APTT,TT.2.Administration of SIO significantly increased C_max、AUC_0→144、AUC_0→∞、t_1/2and significantly decreased CL/F of Warfarin compared with placebo.3.SIO had no clinically significant effect on the pharmacodynamic effects of Warfarin,as assessed 144h after Warfarin dosing by measurement of PT,APTT,TT.更多还原