吲哚美辛5-氟尿嘧啶甲酯的合成及抗肿瘤活性

目的合成吲哚美辛5-氟尿嘧啶甲酯,并对其体内外抗肿瘤活性进行评价。方法以5-氟尿嘧啶及吲哚美辛为主要原料,经2步反应合成目标化合物。应用Hela、HT1080、kB、Heps及Bel-7 402等5种肿瘤细胞系对吲哚美辛5-氟尿嘧啶甲酯体外抗肿瘤活性进行评价;选用小鼠肉瘤S180瘤株、肝癌H22瘤株和Lewis肺癌实体瘤3种瘤株为指标,对吲哚美辛5-氟尿嘧啶甲酯的体内抑瘤活性进行考察。结果经熔点测定及1H-NMR、MS及IR确证目标产物结构,产品收率为66%;吲哚美辛5-氟尿嘧啶甲酯的体外抗肿瘤作用很弱,但对于小鼠S180、H22及Lewis 3种实体瘤的抑制作用与5-氟尿嘧啶相近。结论吲哚美辛5-氟尿嘧啶甲酯为5-氟尿嘧啶的前体药物。     

吲哚美辛5-氟尿嘧啶甲酯的代谢物5-氟尿嘧啶在大鼠体内组织分布和排泄

采用高效液相色谱法对吲哚美辛5-氟尿嘧啶甲酯(indomethacin 5-fluorouracil-1-ylmethyl ester，IFM)的代谢物5-氟尿嘧啶在大鼠体内的分布和排泄进行研究。生物样品经液-液萃取后，以甲醇-水-36%乙酸(3∶96.9∶0.1，v/v)或甲醇-水-36%乙酸(10∶89.9∶0.1，v/v)为流动相，使用Diamonsil^TM C₁₈色谱柱进行分离，检测波长为260 nm。大鼠灌胃IFM 100 mg·kg^-1后， 5-氟尿嘧啶在胃、 小肠、 肝组织中浓度较高，其他组织和血浆中较低。5-氟尿嘧啶从尿液(0～24 h)、粪便(0～48 h)中排泄量分别占给药总量的0.006 5%和0.063%。该方法准确、专属性强，适用于IFM代谢物5-氟尿嘧啶的临床前药代动力学研究。     

吲哚美辛锌胶囊在兔血浆中药代动力学研究

用ＨＰＬＣ测定了兔口服吲哚美辛锌及吲哚美辛胶囊后血浆中吲哚美辛的浓度，其药－时曲线均符合一室开放模型，数据经３Ｐ８７计算机程序处理拟合得吲哚美辛锌及吲哚美辛药动学参数分别为：Ｃｍａｘ２．０８８ｍｇ／Ｌ，２．６６１ｍｇ／Ｌ；Ｔｍａｘ５．２２７ｈ，３．７０４ｈ；Ｋｅ０．１２３ｈ－１，０．１７２ｈ－１；Ｋａ０．２８９ｈ－１，０．４５９ｈ－１；Ｔ２／２（ａ）２．４０１ｈ，１．５０８ｈ；Ｔ１／２（ｅ）５．６１７ｈ，４．０４０ｈ；ＡＵＣ３１．９０５ｍｇ·ｈ／Ｌ，２７．９０３ｍｇ·ｈ／Ｌ。相对生物利用度为１１４％。     

RP-HPLC法测定吲哚美辛5-氟尿嘧啶甲酯原料药含量及有关物质

目的用RP-HPLC法测定吲哚美辛5-氟尿嘧啶甲酯原料药含量和有关物质。方法色谱柱:DiamonsilTMC18(250 mm×4.6 mm,5μm),流动相:甲醇-0.025 mol.L-1醋酸铵(体积比为65∶35)(用冰醋酸调节pH至3.5),流速:1 mL.min-1,检测波长:260 nm,柱温:40℃。结果在选定的色谱条件下,有关物质与主药分离良好,最低检测限2.0μg.L-1,吲哚美辛5-氟尿嘧啶甲酯的质量浓度在5.0~50.0 mg.L-1内线性关系良好(r=0.999 9),平均回收率99.7%,RSD=1.0%。结论该法适用于吲哚美辛5-氟尿嘧啶甲酯原料药含量和有关物质检查。     

大鼠鼻腔吸收吲哚美辛

研究吲哚美辛经大鼠鼻腔给药作用的可行性。方法：用高效液相色谱仪测定血浆中吲哚美辛的药浓变化，比较大鼠吲哚美辛３ｍｇ．ｋｇ＾－１水溶液经口服、静脉与鼻腔给药的吸收特点。结果：鼻腔约药达峰时间为０．０８ｈ，几乎接近于静脉给药；、峰浓度为２０．０ｍｇ．Ｌ＾－１，     

5—氟尿嘧啶协同给药途径的药代动力学研究和临床应用

目的：研究５－氟尿嘧啶（５－Ｆｕ）腹腔、静脉和灌胃３种给药途径化疗的优劣。方法：采用高效液相色谱不比较研究了家兔５－Ｆｕ３种给药途径的药代动力学。结果：大剂量航空给药能在腹腔,门静脉及肝脏提供高浓度药物,且维持时间较长。静脉给药周围血药浓度及门静脉血药浓度均较高,但有效血药浓度维持时间短,灌胃给药后,腹腔液药浓度极低,门静脉血药浓度虽然高于周围血,但吸收极不规则,个体差异较大。组织中药物浓度测定发     

5-氟尿嘧啶磁性白蛋白亚微球在正常及荷瘤小鼠体内的药代动力学与组织分布

5-氟尿嘧啶磁性白蛋白亚微球(5-flourouracil magnetic albumin deuto-microsphere，5-Fu-MAD)是新型靶向给药系统，考察正常及荷瘤小鼠体内的代谢和分布为其临床应用提供参考。采用HPLC方法测定生物样品中5-Fu浓度。采用原子吸收光谱法测定组织铁浓度。结果显示，小鼠尾静脉注射5-Fu原料药及5-Fu-MAD后，于不加或加磁性支架条件下，药代动力学过程均呈一级二室动力学模型。小鼠静脉注射5-Fu各制剂组后5-Fu和Fe的分布以肝脏、肿瘤组织、脾脏、肺脏为高，肾脏、心脏次之，脑组织和肌肉组织最低。正常小鼠的肌肉组织和荷瘤小鼠肿瘤组织给予磁性支架后，分布显著增加(P<0.01)。可见，5-Fu-MAD在小鼠体内的分布具有缓释特征，且对加入了磁性支架的组织具有靶向性。     

吲哚美辛锌的药物动力学研究

本文用ＵＶ法测定健康成人口服吲哚美辛锌、吲哚美辛胶囊剂后的尿药浓度，以酸－碱法提取尿中吲哚美辛原形药，在２６５ｎｍ处测定吸收度，在４～３２ｕｇ／ｍｌ范围内线性关系良好，平均回收率＞９９．０％，日内及日间ＲＳＤ＜０．９２％，对６名健康志愿者口服给药后的药物动力学研究结果：吲哚美辛锌及吲哚美辛的药动学参数分别为，Ｔｍａｘ＝３．３２，１．８７（Ｐ＜０．０１）；Ｋ＝０．１２７３，０．１５３１（Ｐ＜０．０５）；Ｔ１／２＝５．４７，４．６１（ｐ＜０．０５）；Ｘｕ（ｍｇ）＝１０．９１，１３．１４（Ｐ＞０．０５）吲哚美锌的相对生物利用度为８３．０３％。     

Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam

Abstract

1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120?mg/kg, ip).

2. 5-FU was shown to induce hepatic CYP3A2 protein 2?days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1′-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups.

3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CL_tot) and elimination rate constant (k_e) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes.

4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.     

Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil

1.?We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats.

2.?Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (k_e) was significantly decreased without significant change in the volume of distribution at the steady state (Vd_ss).

3.?The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU.

4.?The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU.

5.?These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.     

Hepatic fibrosis does not affect the pharmacokinetics of 5-fluorouracil in rats

In the case of cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil (5‐FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5‐FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5‐FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate‐limiting enzyme in 5‐FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5‐FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5‐FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

Relationship between 5-fluorouracil exposure and outcome in patients receiving continuous venous infusion with or without concomitant radiotherapy

AIMS: Toxicity and response are correlated with plasma 5-fluorouracil (5-FU) concentration in patients treated with 5-FU at a dose of 1000 mg m(-2) day(-1). Head and neck cancer patients are treated with various therapeutic regimens, including chemotherapy with 5-FU at a dose of 600 mg m(-2) day(-1) with radiotherapy. We investigated the plasma concentration-effect relationship for this regimen, with the aim of developing recommendations for dose adjustment. METHODS: Patients received 5-FU at doses of 600 or 1000 mg m(-2) day(-1), as a continuous infusion over 4 or 5 days, with or without radiotherapy for the 600 mg m(-2) day(-1) regimen. The area under the curve (AUC) for 5-FU concentration was estimated, based on a single morning blood sample taken each day during treatment. AUC values were compared between patients with and without toxicity. This simplified method for AUC estimation was compared with the standard two-samples-per-day method in an independent group of 50 patients. RESULTS: Forty-six patients, corresponding to 115 courses, were included in this prospective study. Considerable interindividual variability in estimated AUC was observed for both doses. Grade 3-4 toxicity occurred in 10 and 21% of patients given doses of 600 and 1000 mg m(-2) day(-1), respectively. Ths study confirmed the relationship between plasma 5-FU concentration and toxicity previously reported for 1000 mg m(-2) day(-1), but found no such relationship for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. CONCLUSIONS: Our results do not support the use of therapeutic drug monitoring to improve tolerance for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. A simplified method is proposed for 5-FU monitoring for the 1000 mg m(-2) day(-1) regimen.     

Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients

Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma.A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination.The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.     

HPLC法测定氨糖美辛肠溶片中吲哚美辛的含量

目的：建立ＨＰＬＣ法测定氨糖美辛肠溶片中吲哚美辛的含量。方法：采用ＳＰＨＥＲＩ－５Ｒｐ－１８色谱柱,以甲醇－水－乙腈－磷酸（６０：２５：１５：０．０４）为流动相。结果：吲哚美辛在１０～６０μｇ／ｍｌ范围内深度与峰面 良好的线必ｒ＝０．９９９９）,平均回收率为９９．５６％,ＲＳＤ为０．６５％。结论：本法准确、快速、重现性好。     

The clinical syndrome of 5-fluorouracil cardiotoxicity

Summary 5-fluorouracil (FUra) is one of the most frequently used drugs in cancer treatment, particularly in combination with other agents. Its activity when administered as an infusion rather than a bolus has led to a renewed and increased use. A cardiotoxicity that mimics ischemia has been associated with the administration of FUra in cancer patients. This cardiotoxicity may manifest itself as: (a) dysrythmias with and without cardiorespiratory symptoms (b) ECG changes with and without cardiorespiratory symptoms (c) cardiorespiratory symptoms with and without ECG changes (d) acute myocardial infarct; symptoms and ECG changes (e) ventricular dysfunction (f) cardiogenic shock and (g) sudden death. Several case studies which illustrate the cardiotoxic sequelae that may be associated with the use of this drug are discussed. The incidence, contributing factors, risk factors and mechanisms underlying this phenomenon are undetermined. No appropriate recommendations for monitoring patients or for predicting those patients that will develop such toxicity while receiving FUra can be made at present. Prospective studies to determine the true incidence, spectrum and mechanisms causing this syndrome are ongoing and required for its understanding and prevention.     

高效液相色谱法测定复方吲哚美辛乳膏中吲哚美辛的含量

目的:建立复方吲哚美辛软膏中吲哚美辛含量的高效液相色谱方法。方法:采用 XTerra~C_(18)色谱柱(4.6 mm×150mm,5μm),以 pH 5.0的磷酸盐缓冲液-乙腈(60:40)为流动相,流速为1.0 mL·min~(-1),柱温为30℃,检测波长为320 nm,进样量20μL,用外标法测定。结果:吲哚美辛在6.0～60μg·mL~(-1)范围内线性关系良好(r=0.9999),平均回收率为99.2%,RSD 为0.24%。结论:本方法灵敏度高,操作简便可靠。     

Disposition of 5-fluorouracil during chronic hepatic arterial infusion to patients with carcinoma in the liver and effect on circulating platelets

5-Fluorouracil was administered by continuous hepatic intra-arterial infusion to eight patients with the diagnosis of cancer of the gastrointestinal tract and hepatic metastases. Its elimination characteristics were investigated to see if they correlated with therapeutic effect or reduced clinical toxicity when the drug was given by this route. Urinary excretion of drug and metabolites was similar to findings after intravenous bolus doses. Disposition changes could not be correlated with therapeutic effect or clinical toxicity. A dose-related biphasic effect of 5-fluorouracil was found on circulating platelets. Doses greater than 6 mg kg^?1 d^?1 decreased the number of circulating platelets, while doses less than that resulted in an increase in circulating platelets. Further studies are required to determine the mechanism of the effect of 5-fluorouracil on platelets.