CA4P抗肿瘤作用的实验研究

目的 观察化合物康普瑞丁磷酸二钠(CA4P)对人宫颈癌Hela细胞的体外抑制作用及对裸鼠移植瘤的体内抗癌作用.方法 用MTT法研究CA4P对Hela细胞增殖的影响,将Hela细胞移植于裸鼠皮下,观察肿瘤的生长状况,并计算抑瘤率和脏器系数.结果 CA4P0.5～64μg·mL~(-1)时,对Hela细胞24、48 h的抑制率分别为15%～75%、18%～80%,IC_(50)分别为0.336、0.207μg·mL~(-1);对裸鼠Hela细胞移植瘤的抑制率为30%～50%,且呈量效关系.结论 CA4P对人宫颈癌Hela细胞的增殖具有抑制作用,对裸鼠移植瘤的体内抑制作用明显.     

CA4P脂质体的制备工艺研究

目的 研究CA4P脂质体的处方及制备工艺.方法 以包封率为主要评价指标考察制备方法;用透射电镜和粒径测定仪表征脂质体的形态和粒径;用HPLC法测定脂质体中CA4P的包封率和载药量;以正交设计筛选优化最佳处方工艺.结果 脂质体的平均粒径为167 nm,Zeta电位为-24.3 mV,最佳工艺处方的药-脂比为1:12,磷脂-胆固醇为8:1,有机相-水相体积为4:1,水合介质为0.9%NaCl;制备3批脂质体的平均包封率为58%、载药量为4.8%.结论 逆相蒸发-探头超声法可制备具有较高包封率的CA4P脂质体.     

Combretastatin A4磷酸酯二钠在大鼠体内的药物动力学

目的研究前药Combretastatin A4磷酸酯二钠(CA4P)在大鼠体内生成Combretastatin A4(CA4)的药物动力学。方法采用HPLC法测定iv10、20mg·kg-1CA4P后,大鼠体内不同时间点的原药CA4的血药浓度。药-时数据经DAS统计软件拟合处理。结果两个剂量组的CA4在大鼠体内的过程均符合二室模型,t1/2β分别为34.427±2.849、30.076±3.107min;Vd分别为1.402±0.178、1.568±0.131L·kg-1;Cl分别为0.061±0.003、0.058±0.003L·min-·1kg-1;AUC0-t分别为132.393±3.144、291.872±15.555mg·L-·1min。结论静注CA4P后,CA4在大鼠体内以二室模型的规律快速代谢和消除。     

利福喷丁的临床药物动力学研究

本文报道利福喷丁正常人药物动力学研究结果，健康志愿者１０人单剂口服利福喷丁粉剂及胶囊６００ｍｇ后的体内过程均符合血管外一室模型，其血药峰浓度分别为１７．４３ｍｇ／Ｌ（粉剂）和１８．３８ｍｇ／Ｌ（胶囊），达峰时间为９，７０ｈ（粉剂和）和８．２１ｈ（胶囊），消除半衰期（ｔ１／２ｋｅ）为１９．９０ｈ（粉剂）和１９．４２ｈ（胶囊），以上各项参数经统计学处理均无明显意义，胶囊的相对生物利用度为１０４．７２％，口服该药后有少量自尿中以原形排出体外，给药后２ｈ内分别排出给药量的１１．３０％（粉剂）和１１，２９％（胶囊）。     

抗肿瘤药氟脲脱氧核苷的药物动力学与临床应用

氟脲脱氧核苷 (5- fluoro- 2′- deoxyuridine,flo-xuridine,FUDR)是 Duschinsky等人合成的一种抗代谢类的抗肿瘤药。 FUDR是氟脲嘧啶 (5-fluorouracil,5- FU)的衍生物 ,两者具有相似的抗肿瘤作用机制。在欧美国家的临床应用主要是通过动脉输注用于各种类型肝癌 (尤其是转移性肝癌 )的姑息性治疗 ,并取得了较好的疗效。与 5- FU相比 ,FUDR的化疗指数较高[1] 。目前 ,FUDR在国内的临床应用与研究还处于刚刚起步阶段。1　测定方法迄今为止可用于 FUDR药物动力学研究的行之有效的测定方法并不多。造成这一问题的主要原因有 :1 FUDR…     

早孕妇女口服氟康唑的群体药物动力学研究

目的应用WinNonmix药动学软件计算早孕妇女口服氟康唑150 mg后的群体药物动力学参数,并分析绒毛组织和血液组织中氟康唑的药物浓度相关性。方法以早期妊娠合并阴道假丝酵母菌感染欲行人流术的患者为研究对象,以氟康唑150 mg单剂量口服给药后在不同的时间点行人流术,同时留取实验对象的血液和绒毛组织,测定生物组织中的药物浓度,并进行数据处理。结果研究表明绒毛组织中药物浓度与血液中药物浓度呈正直线相关,直线回归方程为C胚胎=0.364 0×C血液＋0.020 08,相关系数为0.914,P〈0.005。氟康唑在早孕妇女胚胎和血液组织中大约6 d全部代谢完毕,无蓄积。经WinNonmix药动学软件处理,依据非线性混合效应模型计算表明：氟康唑符合一级吸收动力学,有滞后时间的一室模型。固定效应中,体重影响表观分布容积。结论氟康唑在早孕妇女胚胎组织和血液组织中的药物浓度存在显著差异,且符合直线正相关。 更多还原     

没食子酸丙酯在麻醉大鼠体内的药物代谢动力学

用高效液相色谱（ＨＰＬＣ）测定大鼠给予没食子酸丙酯（ＰＧ）３０ｍｇ·ｋｇ－１后０．５，１．５，３．５，７．０，１０．０和３０．０ｍｉｎ的血浆浓度，分析所得血药－时浓度曲线符合二室开放性模型。大鼠ｉｐ双－对硝基苯磷酸酯钠（ＢＮＰＰ）３．４ｍｇ·ｋｇ－１，再ｉｖＰＧ３０ｍｇ·ｋｇ－１，所测ＰＧ血浆浓度与对照组有显著不同，其药物代谢动力学参数ｔ１／２α，ｔ１／２β，ｋ１０，ＡＵＣ以及ＭＲＴ（０－Ｉｎ）均较对照组延长或增加，两组间各参数比较均有显著或非常显著性差异；而ＣＬ也较对照组降低１倍；并且于ｉｖＰＧ５，１０及２０ｍｉｎ后其肝脏及血浆中ＰＧ含量也较对照组增高，两组之间比较均有显著性差异。结果表明ＢＮＰＰ对ＰＧ在大鼠体内的代谢速度有显著影响．     

群体药物动力学研究

近年来,群体药物动力学已引起制剂工业以及美国食品药物管理局(U.S Food and Dring Adminis-tration,FDA)专家们的极大关注,不少FDA法规文件中都引用了群体药物动力学来评价药物的有效性和安全性.本文综述了群体药物动力学研究中的群体方法、实验设计、数据处理和分析以及模型的验证等内容,旨在为药品开发和规范管理提供参考.1 研究背景某些疾病的生理病理特征能有规律地改变剂量-浓度之间的关系.例如主要通过肾消除的药物,肾衰通常会引起病人稳态血药浓度的明显升高.群体药物动力学就是研究个体间血药浓度差异的来源和联系,目的在于揭示引起剂量-浓度关系改变的生理病理因素,确定这种改变的大小,以便拟定合适的临床用药剂量.传统药物动力学的研究对象通常是健康志愿者或经严格挑选的病人,且仅对他们的平均情况感兴趣.对于个体间的差异往往采用复杂的实验设计或     

中药黄药子对大鼠阿霉素药物动力学的影响

目的观察黄药子(DBR)作为抗癌药对大鼠阿霉素(Dox)药物动力学的影响.方法建立测定血浆及尿中Dox浓度的HPLC法,比较试验组及对照组药物动力学参数及血浆蛋白结合率.结果对照组(仅给予Dox)与试验组(给予DBR及Dox)之间的末端除速度常数[β,(0.44±0.23)、(2.48±0.43)h-1],周边室向中央室转运速度常数[k21,(0.580±0.243)、(3.10±0.33)h-1],清除率[Cl,(2.42±0.49)、(1.66±0.48)L/h],表观分布体积[V,(0.14±0.05)、(0.08±0.04)L]及稳态表观分布体积[Vss,(2.09±1.47)、(0.23±0.15)L],存在显著性差异(P＜0.05);相反,血药浓度-时间曲线下面积[AUC,(2.57±0.62)、(3.88±1.31)μg*h/ml],分布速度常数[α,(25.54±7.85)、(26.34±2.55)h-1],中央室消除速度常数[k10,(19.20±8.30)、(21.0±3.20)h-1],中央室向周边室转运速度常数[k12,(6.19±1.39)、(4.66±2.56)h-1],没有显著性差异(P＞0.05),肝功能的结果也显示两组之间GPT水平无显著差异(n=15,P＞0.05).对照组及试验组Dox的浓度为0.06、0.60、6.0μg/ml的血浆蛋白结合率分别为(62.54±2.62)%、(64.83±3.84)%、(65.49±2.36)%及(66.54±2.39)%、(69.47±7.00)%、(73.17±1.76)%.原型Dox在尿中回收率(Xu%)试验组(5.62±0.63)%,显著低于对照组(8.03±0.83)%(P＜0.05).HPLC法对血浆及尿中Dox的最低检测限为0.01μg/ml,血浆中不同浓度提取回收率为90.96%～98.25%,Dox浓度为0.12、0.80、1.40μg/ml的日内及日间相对标准偏差(RSD)均小于6%(n=5).结论DBR与Dox在大鼠体内存在药物动力学的相互作用,DBR主要是影响Dox在组织的分布.     

人口服富硒酵母的药物动力学研究

用金膜电极微分阳极溶出伏安法测定人口服富硒酵母(SEY)后的血浆硒浓度,并用一室模型分析 SEY 在健康人体内的药物动力学参数:半衰期(t_(1/2))3.50 h,吸收速度常数(k_a)0.57h~(-1),消除速度常数(k)0.20h~(-1),药物达峰时间(T_(max))3.39 h,血药浓度-时间曲线下面积(AUC_(0→∞))600 ng/(ml·h)。实验结果显示健康人口服 SEY 10 μgSe/kg 后12 h 从体内基本消除,24 h 后体内完全消除,故在低硒地区按推荐剂量补硒不易引起蓄积中毒。     

CombretastatinA4及其磷酸酯二钠在大鼠体内的药代动力学比较研究

目的：采用LC—MS／MS技术比较研究Combretastatin（CA4）及其磷酸酯二钠（CA4P）前药分别给药于SD大鼠后的药代动力学差异。方法：12只SD大鼠禁食后分别单次尾静脉给予50mg／kgCA4P或36mg／kgCA4（等摩尔量）,采集不同时间点血样,采用LC—Ms／MS方法进行血样药物浓度测定,求算相应的药代动力学参数,并建立CA4P-CA4转化的药动学模型。结果：大鼠单剂量i．v．50mg／kgCA4P或36mg／kgCA4后,CA4P和CA4血浆药物浓度一时间曲线下面积AUC分别为（27126±4142）、（7751±801）、（5037±1433）ng·h·mL-1,消除半衰期t1／2分别为（0．85±0．35）、（1．27±0．33）和（0．95±0．65）h。CA4P和CA4在SD大鼠体内药动学行为均无性别差异。结论：大鼠单剂量i．v．50mg／kgCA4P后,CA4P在体内迅速转化为CA4,相比于直接i．v．36mg／kgCA4,CA4在体内的暴露量（AUC）显著性提高（P〈0．05）,消除半衰期也有所增加,为前药CA4P的药代动力学优势。     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P)

Vascular-disrupting strategies impair a tumor's blood vessel network, which is essential for tumor progression and metastasis. Vascular-disrupting agents (VDAs) cause a rapid and selective vascular shutdown in tumors to produce extensive secondary neoplastic cell death due to ischemia. A lead agent in this therapeutic strategy is the tubulin depolymerizing agent combretastatin-A4 phosphate (CA4P). Used alone, CA4P induces extensive necrosis in a wide variety of preclinical cancer models and significant blood flow reductions in the patient tumors. Preclinical and clinical data further indicate that CA4P can effectively be combined with chemotherapy or radiotherapy. Finally, the potential of combining VDAs with antiangiogenic therapies has shown considerable promise in preclinical models and such combinations are now beginning to be evaluated in patients.     

Pharmacokinetics of oral L-isoidide mononitrate in rats

L-isoidide mononitrate (L-IIMN) is the most potent mononitrate vasodilator described so far in the literature. Since other mononitrates, such as isosorbide-5-mononitrate and isosorbide-2-mononitrate, have been shown not to be subject to first-pass metabolism, we examined the pharmacokinetics of L-IIMN after oral administration to determine whether this compound also exhibited this behavior. An oral dose of 2 mg kg^?1 L-IIMN dissolved in normal saline was given to seven rats. Absorption of L-IIMN after dosing was rapid with an apparent absorption half-life of 9.5 ± 3.6 min (mean ± SD). Plasma L-IIMN concentrations peaked between 5 and 20 min after dosing and declined thereafter in an apparently monoexponential manner. The average elimination half-life was 11.9±1.7 min (mean ± SD). Oral bioavailability was estimated to be about 50%. Thus, unlike the other mononitrates so far examined in the literature, L-IIMN exhibits incomplete bioavailability. This pharmacokinetic behavior, however, is consistent with its faster systemic clearance compared to other organic mononitrates.     

Pharmacokinetics of glucuronidation of propranolol following oral administration in humans

Pharmacokinetic and bioavailability parameters of propranolol were estimated in 10 healthy adult subjects after single oral doses of two commercial tablet formulations of propranolol hydrochloride (2 × 40 mg). Plasma concentrations of propranolol were determined by a high-performance liquid-chromatographic (HPLC) assay. Peak plasma concentrations of propranolol glucuronide were 6·8 times those of the corresponding peak propranolol plasma concentrations. The mean resident time (MRT) of propranolol and of propranolol glucuronide was determined for each subject for both formulations. The MRT of the parent drug was found to be longer than the MRT of the glucuronide metabolite for each of the subjects examined. Statistical moment analysis indicated that this phenomenon is attributable to extensive presystemic glucuronidation of the parent drug.     

Carbon‐14 radiosynthesis of combretastatin A‐1 (CA1) and its corresponding phosphate prodrug (CA1P)

The natural product combretastatin A‐1 (CA1) is isolated from the African bush willow tree, a member of the Combretaceae family. CA1 has important medicinal value, due in part to its ability to inhibit tubulin assembly. The prodrug combretastatin A‐1 diphosphate (CA1P; OXi4503) is currently in human Phase I clinical trials as a vascular disrupting agent. This paper describes the carbon‐14 radiosynthesis of [4′‐¹⁴C]CA1 and the corresponding phosphate prodrug salt [4′‐¹⁴C]CA1P in high specific activity (55 mCi/mmol). The carbon‐14 label was introduced by methylation of the C‐4′ protected phenolic moiety of the CA1 precursor following removal of the tert‐butyldimethylsilyl protecting group in the presence of [¹⁴C]methyl iodide. This was accomplished in excellent yield without significant Z to E isomerization. The [¹⁴C]‐precursor ((Z)‐1‐[3′,[4′‐¹⁴C],5′‐trimethoxyphenyl]‐2‐[2″,3″‐di‐[(isopropyl)oxy]‐4″‐methoxyphenyl] ethene) was subjected to a de‐isopropylation reaction with TiCl₄. The tetrabenzyl phosphate derivative of the resulting diol was prepared using fresh dibenzyl phosphite. Debenzylation with trimethylsilylbromide, followed by hydrolysis of the trimethylsilyl ester and adjustment of the pH with dilute aqueous hydrochloric acid yielded [4′‐¹⁴C]CA1P with an overall radiochemical yield of 8.4%. Copyright © 2009 John Wiley & Sons, Ltd.     

醋酸艾塞那肽在Wistar大鼠体内的药物代谢动力学研究

研究醋酸艾塞那肽（exendin-4）在Wistar大鼠体内的药物代谢动力学，组织分布以及排泄特征。IODOGEN（四氯二苯基苷脲）法制备^125I-exendin-4，大鼠皮下或静脉注射，^125I-exendin-4，以放射性核素示踪动力法检测血液中的药物浓度，由非房室模型评价药物动力学参数。同时研究了大鼠皮下注射^125I-exendin-4后的组织分布和排泄。大鼠皮下注射^125I-exendin-4后Tmax和t1/2分别是（0．25±0．02）h和（1．28±0．14）h，绝对生物利用度为（65．5±10．2）％；^125I-exendin-4的分布快速而广泛，其中以肾脏中最高，而在脑组织中只有微量^125I-exendin-4；^125I-exendin-4主要随尿液排泄。实验结果与国外公布的实验数据基本一致。醋酸艾塞那肽在大鼠中的药物代谢动力学参数为临床试验提供了科学依据。     

Enhanced tamoxifen bioavailability after oral administration of tamoxifen in rats pretreated with naringin

The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of tamoxifen and of its metabolite, 4-hydroxytamoxifen in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined by HPLC after pretreating with naringin (1.5, 7.5, and 15 mg/kg) 30 min before orally administering tamoxifen (10 mg/kg). Compared with the control group (treated with tamoxifen alone), naringin pretreated animals showed significantly (p<0.01) increased areas under the plasma concentration-time curves (AUC) and peak tamoxifen concentrations (C_max). The absolute bioavailabilities (AB%) of tamoxifen in naringin pretreated animals were enhanced versus control (from 32.8% to 47.1%), and the relative bioavailabilities (RB%) of tamoxifen in the naringin pretreated groups were 2.02–2.88 times higher than that in the control. No significant changes in the terminal half-life (t_1/2) or T_max of tamoxifen were observed in the naringin pretreated groups. The AUCs of 4-hydroxytamoxifen after pretreating naringin were also significantly elevated (p<0.05) versus the control. But metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower. These results suggest that the enhanced bioavailability of tamoxifen in the presence of naringin might be due to the inhibition of CYP3A4 by naringin. If the results of this study are further confirmed by clinical trials, tamoxifen dosages should be adjusted to avoid potential drug interaction when tamoxifen is used clinically in combination with naringin-containing dietary supplements.     

Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects

Pharmacokinetics of sildenafil after intravenous and oral administration at various doses and first-pass effect at 30 mg/kg were evaluated in rats. After intravenous administration (10, 30, and 50 mg/kg), the dose-normalized AUC values were proportional to intravenous doses studied. However, after oral administration (10, 30, and 100 mg/kg), the dose-normalized AUC values increased significantly with increasing doses, possibly due to saturation of metabolism of sildenafil in rat intestinal tract. After oral administration (30 mg/kg), approximately 0.626% was not absorbed and F was 14.6%. The AUC after intragastric administration was significantly smaller (71.4% decrease) than that after intraportal administration, however, the values were not significantly different between intragastric and intraduodenal administration. The above data suggested that intestinal first-pass effect of sildenafil was approximately 71% of oral dose in rats. The AUC values after intraportal administration were significantly smaller (49% decrease) than that after intravenous administration. This suggested that hepatic first-pass effect of sildenafil after absorption into the portal vein was approximately 49% of oral dose in rats (approximately 49% was equivalent to approximately 13.7% of oral dose). The low F of sildenafil at a dose of 30 mg/kg in rats could be mainly due to considerable intestinal first-pass effect.     

Pharmacokinetics of ketotifen after oral administration to healthy male subjects.

The pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross-over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC-MS method. The limit of quantitation was 40 pg ml-1. Inter-day precision and accuracy calculated from quality control samples were 16.3 per cent (-1.9 per cent), 19.8 per cent (+4.5 per cent) and 23.6 per cent (+5.9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml-1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml-1 after the syrup formulations and 300 pg ml-1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half-life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.