千金藤素对非索非那定肠吸收的影响

目的 研究千金藤素对非索非那定大鼠肠吸收的影响.方法 采用大鼠肠外翻模型,以维拉帕米为阳性对照,研究千金藤素对非索非那定肠吸收的影响,并用反相高效液相色谱法测定大鼠肠黏膜内外两测的非索非那定浓度.结果 非索非那定在大鼠十二指肠有吸收,千金藤素能增加非索非那定的吸收.结论 千金藤素能增加非索非那定吸收,机制可能是抑制了P...     

千金藤素对大鼠体内非索非那定药动学的影响

目的研究千金藤素对大鼠体内非索非那定药动学的影响。方法SD大鼠10只随机分为两组,分别灌胃给予非索非那定、千金藤素+非索非那定,不同给药时间采集血样。采用高效液相色谱法测定非索非那定血药浓度,绘制药物浓度 时间曲线,用3P97药动学软件拟合药动学参数,并进行统计分析。结果非索非那定和千金藤素+非索非那定组Cmax分别为（1.225±0.770）,（1.417±0.440） μg•mL 1 （P＜0.05）;AUC0 t分别为（5.379±1.570）,（8.088±1.760） mg•h•L 1（P＜0.01）。千金藤素＋非索非那定组AUC0 t和Cmax分别增加7.09%（P＜0.05）和15.67%（P＜0.05）;两组Ka、 MRT和t1/2差异无统计学意义。结论与千金藤素合用后,非索非那定在大鼠体内的生物利用度增加,千金藤素对非索非那定在大鼠体内药动学具有显著影响。     

千金藤素在大鼠肠道内的吸收动力学

目的 考察千金藤素在大鼠肠道内的吸收动力学.方法 采用大鼠在体肠吸收方法, 用HPLC对循环液中的千金藤素进行分析.结果 千金藤素在大鼠肠道内无特定吸收部位,全肠道均有较好吸收.十二指肠、空肠、回肠、结肠的每小时吸收百分率(中浓度)分别为16.99%、17.09%、18.00%、15.4%.不同浓度千金藤素在大鼠肠道内的吸收速率常数ka经方差分析无显著性差异(P＞0.05),千金藤素吸收机理为被动扩散.结论 千金藤素在整个肠道内均有吸收,其口服制剂应以提高生物利用度为主要目标.     

非索非那定大鼠体内药代动力学研究

目的建立高效液相色谱法（HPLC）研究非索非那定灌胃给药后非索非那定体内药动学特点。方法采用HPLC测定,色谱柱为DikmaTMC18（4.6mm×250mm,5μm）,流动相：乙腈-0.5%磷酸二氢钾（pH3.8）-三乙胺（30∶70∶0.3）,流速：1.2ml/min,检测波长：220nm,检测非索非那定大鼠灌胃后药代动力学参数。结果非索非那定的药动学模型为二室模型,其药动学参数为Ka=1.689h-1,Cmax=1.225μg/ml,Tmax=1.8h,MRT=5.013h,t1/2α=1.018h。结论高效液相色谱法研究非索非那定大鼠灌胃给药后体内药代动力学,方法预处理简单、专属性强,结果可靠。     

抗组胺药非索非那定的研究进展

非索非那定是第二代H1抗组胺药,对H1受体有高度选择性,有直接的抗炎活性,起效快、作用维持时间长且长期使用不易出现耐药性.非索非那定的代谢动力学易受几种转运蛋白诱导剂或抑制剂的影响,但未见需调整剂量的报道,转运蛋白对非索非那定代谢的机理有待进一步的研究.临床用于治疗变态反应性疾病,如过敏性鼻炎、荨麻疹、过敏性哮喘、遗传性过敏性斑秃等,且联合其他药物疗效显著.目前,非索非那定微球的鼻内给药制剂正在研发中.非索非那定不良反应少见,无论是单独应用还是联合其他药物使用,都未见严重的心血管事件,不影响胆碱能活性.非索非那定不能透过血脑屏障、不进入中枢神经系统,被推荐于从事安全相关作业人员使用.     

MORA生物共振治疗仪联合非索非那定治疗变应性鼻炎80例

目的探讨MORA生物共振治疗仪联合非索非那定治疗变应性鼻炎的疗效。方法将160例患者按接诊时间先后顺序编号,随即分为MORA生物共振治疗仪联合非索非那定治疗组和非索非那定对照组各80例。结果在治疗2周末,两组对比P〉0.05,无统计学意义。而4、6、8周末两组对比P〈0.05有统计学意义。治疗结束后,治疗组总有效率91.5%,而对照组71.8%,两组对比P〈0.05有统计学意义。结论 MORA生物共振治疗仪联合非索非那定治疗变应性鼻炎与单纯应用非索非那定治疗变应性鼻炎相比较,症状、体征、治愈率等长期效果方面,前者明显好于后者。     

非索非那定的微生物转化制备

研究了以普拉特链霉菌SIPI-76微生物转化特非那定为非索非那定的条件。考察碳源、氮源等培养基成分，底物的加入浓度、时间，生长细胞培养时的pH、温度、溶氧等参数对转化的影响。表明在优化条件下转化率达到90％。     

抗组胺药非索非那定盐酸盐的合成

目的研究抗组胺药非索非那定盐酸盐(fexofenadine hydrochloride)的合成.方法以2-甲基-2-苯基丙酸为起始原料,通过氯化、胺化、傅-克酰基化、缩合、还原、水解及成盐7步反应,合成得到非索非那定盐酸盐(1).结果与结论以总产率为38.1%合成得到非索非那定盐酸盐,其结构经核磁(1H-NMR)和质谱(MS)确证.本法具有原料价廉易得、反应条件温和、操作简便等优点.适合于工业化生产.     

卡介菌多糖核酸联合非索非那定对慢性荨麻疹疗效及血IgE影响的研究

目的观察卡介菌多糖核酸注射液联合非索非那定治疗慢性荨麻疹的疗效及对血液IgE变化的影响。方法将85例慢性荨麻疹患者随机分为治疗组和对照组,2组均给予非索非那定口服,治疗组加用卡介菌多糖核酸注射液肌内注射。观察临床疗效及比较治疗前后血液IgE变化。结果联合治疗组有效率、痊愈率明显高于对照组（P〈0．05）,同时联合治疗组血液IgE恢复正常水平较快（P〈0．05）。结论卡介菌多糖核酸核酸联合非索非那定治疗慢性荨麻疹疗效显著。     

非索非那定联合孟鲁司特治疗儿童上气道咳嗽综合征疗效观察

目的:观察非索非那定联合孟鲁司治疗儿童上气道咳嗽综合征的临床疗效及安全性.方法:112例儿童上气道咳嗽综合征(UACS)患者按随机数字表分为观察组和对照组各56例.观察组手非索非那定片30 mg,po,bid,孟鲁司特钠片5 mg,po,qn.对照组给予非索非那定片30 mg,po,bid.观察两组疗效及药品不良反应.结果:观察组总有效率96.4％,对照组总有效率80.4％,两组比较差异有统计学意义(P＜0.05).观察组患者在3d、7d咳嗽消失及平均咳嗽消失时间明显优于对照组(P＜0.05),均未出现明显不良反应.结论:非索非那定联合孟鲁司治疗儿童上气道咳嗽综合征的临床疗效及咳嗽消失情况优于单用非索非那定.     

外翻肠囊法研究姜黄素促进葫芦素B肠段吸收作用

目的:建立大鼠肠吸收模型,考察对葫芦素B的吸收以及姜黄素对葫芦素B吸收的促进作用。方法:采用大鼠离体外翻肠囊模型,通过HPLC法测定肠囊内样品溶液中葫芦素B的含量,研究葫芦素B在不同肠段的吸收特性和不同比例姜黄素对葫芦素B的促吸收作用。结果:葫芦素B的肠吸收随其浓度的升高而增大,当葫芦素B联合不同比例姜黄素后,百分吸收率(P%)、累计吸收量(Q)和吸收速率常数K_a值均具有显著性差异。结论:葫芦素B主要吸收部位为十二指肠,且在大鼠肠内主要以被动扩散方式吸收;姜黄素能够促进葫芦素B的大鼠肠吸收,且呈浓度依赖性。     

外翻肠囊法评价及比较5种药物大鼠肠透膜能力

目的:考察外翻肠囊法在评价及比较多种药物肠透膜能力方面的可行性与实用性。方法:按外翻肠囊法制备大鼠肠吸收离体模型,测定西酞普兰、布洛芬、酮洛芬、氯霉素、盐酸地尔硫5种药物的累积吸收率,并与该5种药物经脂质体毛细管电泳(LCE)法所测得的脂水分配系数(logP)排序结果比较。结果:5种药物在大鼠小肠壁均有不同程度的吸收,累积吸收率由高至低依次为西酞普兰>盐酸地尔硫>布洛芬>酮洛芬>氯霉素,与LCE法测定结果一致。结论:外翻肠囊法可评价及比较多种药物的肠透膜能力。     

广枣提取物大鼠肠外翻的吸收研究

目的研究广枣提取物中2种主要代表性成分没食子酸和原儿茶酸在大鼠不同肠段、不同时间的吸收规律。方法构建大鼠肠外翻模型,应用HPLC法测定广枣提取物肠吸收液中没食子酸和原儿茶酸含量,计算其吸收参数,并分析其在大鼠小肠不同部位、不同时间的吸收特征。结果 2.5h为肠外翻最终检测时间点,在建立的分析色谱条件下,没食子酸和原儿茶酸色谱峰处台氏液和广枣提取物中其他成分对其无干扰,专属性良好。广枣提取物中原儿茶酸和没食子酸在各肠段均为线性吸收,r2值均达到0.90以上,不同肠道部位的累计吸收结果为:十二指肠>空肠>回肠>结肠。结论广枣提取物中原儿茶酸和没食子酸在肠道的吸收特征符合零级吸收速率,其最佳吸收部位为十二指肠。     

Enteric Excretion of Baicalein,a Flavone of Scutellariae Radix,via Glucuronidation in Rat: Involvement of Multidrug Resistance-Associated Protein 2

PURPOSE: Baicalin (BG) and its aglycone, baicalein (B), are strong antioxidants and have various pharmacological actions. The purpose of this study was to evaluate efflux of BG from rat intestinal mucosal cell following glucuronidation of B absorbed after oral administration of B. METHODS: The absorption and excretion of BG and B were evaluated in rats using the in situ jejunal loop technique and in vitro jejunal everted sac experiments. BG and B levels were determined by high-performance liquid chromatography with electro-chemical detection to ensure selectivity and high sensitivity. RESULTS: A large amount (30.4% recovery) of BG, but no B, was detected in the intestinal lumens of germ-free rats 4 h after oral administration of B (12.1 mg/kg), in comparison with a substantial recovery (55.1%) of unabsorbed BG 4 h after its administration. During the in situ rat jejunal loop absorption experiment, B disappeared rapidly, and 8% of the lost B was excreted into the loop as BG 20 min after infusing 0.1 mM B. In an in vitro absorption experiment using everted rat jejunal sac, BG also appeared outside the sac, accompanied by the disappearance of B from the outer (mucosal) side. However, very little of B was transferred to the inner (serosal) side of the sac, and only a trace of BG was detected inside the sac. Thus, in both the loop and the everted sac systems, the efflux of BG from the mucosal surface was saturated with the concentration of B added. Moreover, the efflux rate of BG in the everted jejunal sac from Eisai hyperbilirubinemic rat (EHBR) was significantly lower by 56.4% than that from Sprague-Dawley rat. CONCLUSIONS: These results indicate that, in rat, a large proportion of any B absorbed is retained, transformed into BG within the intestinal mucosal cells, and coordinately excreted through multidrug resistance-associated protein 2 (MRP2) into the intestinal lumen.     

Everted gut sac model as a tool in pharmaceutical research: limitations and applications

Objectives This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction. Key findings The mechanism of drug absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also. Summary The everted sac model is an efficient tool for studying in‐vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.     

The involvement of P-glycoprotein in berberine absorption

Berberine is an important ingredient in a number of traditional Chinese medicines but has been shown to have poor bioavailability in the dog. The aim of this study was to use the P-glycoprotein (P-glycoprotein) inhibitors cyclosporin A, verapamil and the monoclonal antibody C219 in in vivo and in vitro models of intestinal absorption to determine the role of P-glycoprotein in berberine absorption. In the rat recirculating perfusion model, berberine absorption was improved 6-times by P-glycoprotein inhibitors. In the rat everted intestinal sac model, berberine serosal-to-mucosal transport was significantly decreased by cyclosporin A. In Ussing-type chambers, the rate of serosal-to-mucosal transport across rat ileum was 3-times greater than in the reverse direction and was significantly decreased by cyclosporin A. In Caco-2 cells, berberine uptake was significantly increased by P-glycoprotein inhibitors and by monoclonal antibody C219. P-glycoprotein appears to contribute to the poor intestinal absorption of berberine which suggests P-glycoprotein inhibitors could be of therapeutic value by improving its bioavailability.     

Gastrointestinal absorption of inorganic mercuric compounds in vitro

Effects of intraluminal pH on the intestinal absorption and tissue binding of HgCl2 and HgO were studied in the everted sac of rat small intestine. The sac was incubated in media containing HgCl2 or HgO (10(-5 M] at different pH values. With an increase in pH, the uptake of HgCl2 in the intestinal tissue decreased and the transport of HgCl2 through the tissue increased. Similar pH dependence was observed in the uptake of HgO. The transport of HgCl2 seemed to be correlated with mercury bound to a protein (molecular weight between 440,000 and 669,000) and to be inversely correlated with that bound to intestinal metallothionein. These results suggest that the increase of intraluminal pH promotes the absorption of HgCl2 accompanied by a change in the binding of HgCl2 to the everted tissue sac.     

Changes in Intestinal Mucosal Permeability Caused by Nonprotein Thiol Loss in Rats

The barrier selectivity of the intestinal mucosal membrane permeability may be impaired in certain disease conditions. Membrane permeability was previously shown to be correlated with changes in nonprotein thiol in rat intestinal tissue by the everted sac method. In the present study, the mucosal effects of alloxan-induced diabetes and chronic alcohol administration to intact rats, as well as pre-treatment with diethyl maleate, ethanol, and salicylate, were investigated. In each case, a drop of mucosal nonprotein thiol was associated with an increased absorption of cefoxitin, cefmetazole, and phenol red, hydrophilic compounds that are poorly absorbed through intact membrane, and with a decreased absorption of L-phenylalanine. The effect of nonprotein thiol loss on rectal absorption of cefoxitin, cefmetazole, and phenol red was greater than that on the small intestinal absorption. The increase in phenol red absorption by diethyl maleate in the in vitro everted sac method correlated with Ca²⁺ release from the intestinal mucosa, which was induced by nonprotein thiol loss. Resistance to the effect of nonprotein thiol loss on Ca²⁺ homeostasis was greater in rat ileum than in rat colon (including rectum). The administration of cysteamine as an exogenous nonprotein thiol restored non-protein thiol levels in the mucosa along with the barrier function of the intestinal mucosa to the absorption of cefoxitin, cefmetazole, and phenol red. In contrast, the transport of L-phenylalanine in the small intestinal mucosa was not restored by cysteamine treatment.     

Effects of Grapefruit Juice and Orange Juice on the Intestinal Efflux of P-Glycoprotein Substrates

Purpose. The aim of this study is to investigate the effects of 50% ethyl acetate extracts of grapefruit juice (GFJ) and orange juice (OJ) on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. Methods.The efflux of P-gp substrates from rat everted sac in the absence or presence of verapamil, GFJ, OJ or erythromycin was measured. Rhodamine123, fexofenadine and saquinavir were used as P-gp substrates. P-gp expression levels in the rat jejunum and ileum were determined by Western blot analysis. Results. The efflux of rhodamine123 from the everted sac increased from the apex of the jejunum to the low ileum and the expression of P-gp in the ileum was 2.31-fold higher than that in the jejunum. Verapamil and the 50% GFJ and OJ extracts inhibited the efflux from the intestine of all three drugs tested. Erythromycin decreased the efflux of rhodamine123 and fexofenadine, but did not affect the efflux of saquinavir in the intestine. Conclusions. GFJ and OJ extracts inhibited the efflux of P-gp substrates from the small intestine. Therefore, they may enhance the oral bioavailability of P-gp substrates by increasing absorption in the small intestine.     

Studies on the in vitro absorption of spice principles--curcumin, capsaicin and piperine in rat intestines.

A comparative evaluation of the absorbability of three structurally similar and physiologically active spice principles in an in vitro system consisting of everted rat intestinal sacs was made. When everted sacs of rat intestines were incubated with 50-1000 microg of curcumin in 10 ml incubation medium, absorption of the spice principle was maximum at 100 microg concentration. The amount of absorbed curcumin present in the serosal fluid was negligible. This and the comparatively lower recovery of the original compound suggested that curcumin to some extent undergoes a modification during absorption. For similar concentrations of added piperine, about 44-63% of piperine disappeared from the mucosal side. Absorption of piperine which was maximum at 800 microg per 10 ml was about 63%. The absolute amounts of piperine absorbed in this in vitro system exceeded the amounts of curcumin. The absorbed piperine could be traced in both the serosal fluid and in the intestinal tissue, indicating that piperine did not undergo any metabolic change during the process of absorption. 7-12% of the absorbed piperine was found in the serosal fluid. When everted sacs of rat intestines were incubated with 10-500 microg of capsaicin, a maximum of 82-88% absorption could be seen in the lower concentrations, and the amount of absorbed capsaicin did not proportionately increase at higher concentrations. A relatively higher percentage of the absorbed capsaicin could be seen in the serosal fluid as compared to curcumin or piperine. When these spice active principles were associated with mixed micelles, their in vitro intestinal absorption was relatively higher. Curcumin absorption in everted intestinal sac increased from 48.7% to 56.1% when the same was present in micelles. In the case of capsaicin and piperine, increase in absorption was 27.8-44.4% and 43.4-57.4%, respectively, when they were present in micelles as compared to its native form.