HPLC法同时测定姜黄胶囊中姜黄素和胡椒碱的含量

目的:建立同时测定姜黄胶囊中姜黄素和胡椒碱的HPLC法。方法:采用HPLC检测方法,色谱柱为KromasilC18(250 mm×4.6 mm,5μm),流动相为1%柠檬酸-四氢呋喃(55∶45),用45%氢氧化钾溶液调节pH=3.0,流速为1.0mL/min,检测波长343 nm。峰面积外标法同时测定姜黄胶囊中姜黄素和胡椒碱的含量。结果:姜黄素和胡椒碱的线性范围分别为2.0~80μg/mL(r=0.999 9)和0.1~20μg/mL(r=0.999 9);加样回收率姜黄素为99.62%,RSD为0.69%;胡椒碱为99.17%,RSD为1.14%。结论:该方法具有快速、简便、准确等优点,可用于姜黄胶囊的质量控制。     

复方自微乳中姜黄素和胡椒碱的体外释放研究

目的 考察复方自微乳中姜黄素和胡椒碱的体外释放行为.方法 采用动态透析法,分别以pH值为4.8、7.5的磷酸盐缓冲液并加入0.75％吐温-80作为漏槽条件,考察姜黄素和胡椒碱的体外释放特性.结果 姜黄素在pH 4.8和pH 7.5释放介质中108 h累积释放百分率分别为94.85％和84.38％.胡椒碱在上述介质中36...     

Mechanism of deltamethrin induced thymic and splenic toxicity in mice and its protection by piperine and curcumin: in vivo study

Deltamethrin (DLM) is a well-known pyrethroid insecticide which is widely used in the agriculture and home pest control due to restriction on the sale of organophosphate. DLM induced apoptosis is well known but its mechanism is still unclear. This study has been designed to find out its mechanism of apoptosis with the help of computational methods along with in vivo methods. The QikProp and ProTox results have shown that DLM has good oral absorption. The docking results reveal that DLM has a strong binding affinity toward the CD4, CD8, CD28 and CD45 receptors. Further, to understand the toxicity of DLM on lymphoid cells, a single dose of DLM (5?mg/kg, oral for seven days) has been administered to male Balb/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (caspase-3 activity, DNA fragmentation) have been assessed in thymic and splenic single cell suspensions. Lowering of body weight, cellularity and loss in cell viability have been observed in DLM treated mice. The significant increase in ROS and GSH depletion in spleen and thymus, indicate the possible involvement of oxidative stress. The spleen cells appear more susceptible to the adverse effects of DLM than thymus cells. Further, for the amelioration of its effect, two structurally different bioactive herbal extracts, piperine and curcumin have been evaluated and have shown the cytoprotective effect by inhibiting the apoptogenic signaling pathways induced by DLM.     

Effect of a herbal extract containing curcumin and piperine on midazolam,flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

Aims

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer''s dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers.

Methods

A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing.

Results

Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C_max, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively).

Conclusion

The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.     

Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs

The objective of the present study was to evaluate the effects of curcumin alone and with adjuvant piperine against benzo(a)pyrene (BaP) induced oxidative stress in lungs of male Swiss albino mice. Mice were pretreated either with curcumin (100?mg/kg body weight), or piperine (20?mg/kg body weight), and in combination of both for one week, followed by single dose of benzo(a)pyrene (125?mg/kg body weight) treatment. Treatment with benzo(a)pyrene resulted in increased levels of lipid peroxides (LPO), protein carbonyl content (PCC) and with consequent decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and reduced glutathione (GSH), which however, were increased significantly following curcumin treatment, but the increase was more pronounced when piperine was used as an adjuvant. BaP treatment alone did not alter significantly the GST activity. Pretreatment with curcumin increased the GST activity in BaP treated group, which was enhanced further upon synergistic treatment with piperine and curcumin. Therefore, combined administration of curcumin and piperine shall prove to be more effective in attenuating BaP induced toxicity.     

Preparation,characterisation and evaluation of curcumin with piperine-loaded cubosome nanoparticles

Abstract

Objective: In this study, curcumin was designed into the nanoformulation called cubosome with piperine in order to improve oral bioavailability and tissue distribution of curcumin. Methods: The characteristic of the cubosome was studied by using scanning electron microscope (SEM), Infrared spectrum and small angle X-ray scattering (SAXS) techniques. Tissue distribution of cubosome was measured by liquid chromatography-mass spectrometry (LC-MS) method in mice. Results: The characteristic of the cubosome was demonstrated that the curcumin and piperine were encapsulated in the interior of the cubosome and the crystal form was Pn3m space. The pharmacokinetic test revealed that the cubosome could improve the oral bioavailability significantly compared to the suspension of curcumin with piperine and be mainly absorbed by the spleen. Conclusion: These findings provide the reference to a preferable choice of the curcumin formulation and contribute to therapeutic application in clinical research.     

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin

Introduction: Curcumin is a safe, affordable and natural bioactive molecule of turmeric (Curcuma longa). It has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its lack of aqueous solubility and poor bioavailability. To mitigate the above limitations, recently various nanostructured water-soluble delivery systems were developed to increase the solubility and bioavailability of curcumin.

Areas covered: Major reasons contributing to the low bioavailability of curcumin appear to be owing to its poor solubility, low absorption, rapid metabolism and rapid systemic elimination. The present review summarizes the strategies using curcumin in various nanocarrier delivery systems to overcome poor solubility and inconsistent bioavailability of curcumin and describes the current status and challenges for the future.

Expert opinion: The development of various drug delivery systems to deliver curcumin will certainly provide a step up towards augmenting the therapeutic activity of curcumin thereby increasing the solubility and bioavailability of curcumin. However, the future of such delivery technology will be highly dependent on the development of safe, non-toxic and non-immunogenic nanocarriers.     

姜黄素在大鼠体内药代动力学和生物利用度研究

目的研究姜黄素不同给药途径在大鼠体内的药代动力学和绝对生物利用度。方法建立大鼠血浆中姜黄素的HPLC检测方法。考察大鼠分别经灌胃ig(200 mg·kg-1)、ip腹腔注射(20 mg·kg-1)、舌下静脉iv(10 mg·kg-1)给予姜黄素后血药浓度变化。用DAS2.0软件计算药动学参数,根据腹腔注射、灌胃和静脉给药药-时曲线下面积AUC(0-∞)和给药剂量,计算腹腔注射和口服姜黄素的绝对生物利用度。结果姜黄素浓度在0.05～6.00 mg·L-1范围内线性关系良好(r=0.9998);定量下限为0.05 mg·L-1;低(0.10 mg·L-1)、中(1.00 mg·L-1)、高(4.00 mg·L-1)3个浓度的回收率分别为(99.29±5.40)%、(104.21±4.72)%和(99.83±1.97)%;日内RSD分别为4.49%、3.90%和1.72%,日间RSD分别为4.61%、4.27%和2.00%。大鼠经灌胃、腹腔注射和静脉注射姜黄素后,姜黄素在大鼠体内的代谢过程均符合二室模型,消除半衰期分别为(159.28±18.12)、(90.79±11.55)和(11.96±2.64)min;AUC(0-∞)分别为(86.36±12.90)、(73.39±8.72)、(104.62±11.89)mg.min.L-1。按剂量折算,姜黄素经腹腔注射给药的绝对生物利用度为35.07%,灌胃给药的绝对生物利用度为4.13%。结论姜黄素经不同途径给药在大鼠体内的药代动力学过程相似,腹腔注射给药的绝对生物利用度较高,口服生物利用度低。     

Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS

1.?The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation.

2.?The pharmacokinetic profiles of RA between oral administration of RA (50?mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80?mg/kg) to rats were investigated via a validated UPLC/MS/MS method.

3.?The AUC and C_max of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80?mg/kg PP (p?4.?This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA.     

Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry

An amorphous solid dispersion (SD) of curcumin (Cur) with disodium glycyrrhizin (Na₂GA) was prepared by mechanical ball milling. Curcumin loaded micelles were self-formed by Na₂GA when SD dissolved in water. The physical properties of Cur SD in solid state were characterized by differential scanning calorimetry, X-ray diffraction studies, and scanning electron microscope. The characteristics of the sample solutions were analyzed by reverse phase HPLC, UV–visible spectroscopy, ¹H NMR spectroscopy, gel permeation LC, and transmission electron microscopy. In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87?MG cells than free Cur. Besides, an improvement of membrane permeability of Cur SD was confirmed by parallel artificial membrane permeability assay. Further pharmacokinetic study of this SD formulation in rat showed a significant ～19-fold increase of bioavailability as comparing to free Cur. Thus, Cur SD provide a more potent and efficacious formulation for Cur oral delivery.     

姜黄素纳米混悬液的制备及体内药动学

目的 优化处方工艺,制备稳定的姜黄素纳米晶混悬液,以提高溶出和生物利用度.方法 通过Box-Behnken设计优化姜黄素纳米晶混悬液的处方工艺,并监测粒度和电位的稳定性,通过差示扫描量热分析(DSC)和X射线粉末衍射分析(XRPD)考察研磨前后晶型变化,并通过体外溶出和大鼠体内药动学评价该制剂的体内外释放特征.结果 最...     

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro,in vivo and in situ intestinal permeability studies

Abstract

The main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed C_max1, C_max2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2- and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p?<?0.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.     

姜黄素的药动学特征及剂型改造研究进展

姜黄素（curcumin）是从郁金、姜黄、莪术等姜科植物中提取的一种酚类化合物。大量研究表明,姜黄素具有稳定性差、口服难吸收、易代谢、生物利用度低等特点,而药剂学改造是目前广大研究者用于提高姜黄素生物利用度的重要方法之一。本文就姜黄素及经药剂学改造后的姜黄素的药动学研究作一综述。     

HPLC法测定蒙药那如-3丸中胡椒碱的含量

目的建立蒙药那如 3中胡椒碱的含量测定方法。方法反相高效液相色谱法。采用Hyper silC18色谱柱 ;以甲醇 水 (V∶V =77∶2 3 )为流动相 ;流速为 1 0mL·min-1;柱温为室温 ;检测波长为3 43nm ;进样 2 0 μL;外标法计算含量。结果胡椒碱在 1 2～ 84mg·L-1内峰面积与对照品质量浓度呈良好线性关系 ,其回归方程为A =1 64× 1 0 5ρ -9 9× 1 0 3 ,r =0 9998,其平均回收率为1 0 1 4% ,RSD为 1 4% (n=9)。结论方法简便、准确 ,为那如 3的质量控制提供了方法。     

Sulfation of 6-hydroxymelatonin,N-acetylserotonin and 4-hydroxyramelteon by the human cytosolic sulfotransferases (SULTs)

1.?This study aimed to investigate the involvement of sulfation in the metabolism of 6-hydroxymelatonin (6-OH-Mel), N-acetylserotonin (NAS) and 4-hydroxyramelteon (4-OH-Ram), and to identify and characterize the human cytosolic sulfotransferases (SULTs) capable of sulfating these drug compounds.

2.?A systematic analysis using 13 known human SULTs revealed that SULT1A1 displayed the strongest activity in catalyzing the sulfation of 6-OH-Mel and 4-OH-Ram, whereas SULT1C4 exhibited the strongest sulfating-activity towards NAS. pH-dependence and kinetic parameters of these SULT enzymes in mediating the sulfation of respective drug compounds were determined. A metabolic labeling study showed the generation and release of [³⁵S]sulfated 6-OH-Mel, NAS and 4-OH-Ram by HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells labeled with [³⁵S]sulfate in the presence of these drug compounds. Cytosols of human lung, liver, kidney and small intestine were examined to verify the presence of 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activity in vivo. Of the four human organ samples tested, small intestine and liver cytosols displayed considerably higher 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activities than those of lung and kidney.

3.?Collectively, these results provided a molecular basis for the metabolism of 6-OH-Mel, NAS and 4-OH-Ram through sulfation.     

Sulfation of benzyl alcohol by the human cytosolic sulfotransferases (SULTs): a systematic analysis

The aim of the present study was to identify human cytosolic sulfotransferases (SULTs) that are capable of sulfating benzyl alcohol and to examine whether benzyl alcohol sulfation may occur in cultured human cells as well as in human organ homogenates. A systematic analysis revealed that of the 13 known human SULTs, SULT1A1 SULT1A2, SULTA3, and SULT1B1 are capable of mediating the sulfation of benzyl alcohol. The kinetic parameters of SULT1A1 that showed the strongest benzyl alcohol‐sulfating activity were determined. HepG2 human hepatoma cells were used to demonstrate the generation and release of sulfated benzyl alcohol under the metabolic settings. Moreover, the cytosol or S9 fractions of human liver, lung, kidney and small intestine were examined to verify the presence of benzyl alcohol sulfating activity in vivo. Copyright © 2015 John Wiley & Sons, Ltd.     

Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin

This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P‐glycoprotein (P‐gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC₅₀) of 2.7 µM . In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine‐123 in MCF‐7/ADR cells overexpressing P‐gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and C_max) of etoposide. Consequently, the extent of absolute oral bioavailability (F) of etoposide with curcumin was significantly enhanced compared with that in the control group. In contrast, curcumin did not affect the pharmacokinetics of etoposide after intravenous administration. Therefore, the enhanced oral bioavailability of etoposide in the presence of curcumin might be due mainly to inhibition of the P‐gp efflux pump in the small intestine and possibly by reduced first‐pass metabolism of etoposide in the small intestine by inhibition of CYP3A activity in rats. The combined use of curcumin may be helpful to improve the F of etoposide in chemotherapeutic applications. Copyright © 2011 John Wiley & Sons, Ltd.     

姜黄素对前列腺特异抗原基因表达的抑制

目的研究姜黄素对前列腺特异抗原(PSA)表达的影响。方法化学发光法检测不同浓度的姜黄素处理前列腺癌细胞株LNCap后PSA含量，利用荧光素酶报告基因pGL-3构建含PSA基因5′侧启动子区640 bp DNA的荧光素酶表达载体pGL3-PSA，并将其转染LNCap细胞，不同浓度姜黄素作用24 h后应用荧光素酶测定系统检测荧光素酶表达活性。Western blotting检测姜黄素处理过的LNCap细胞雄激素受体(AR)的表达。结果姜黄素抑制PSA、荧光素酶和AR受体的表达,并有浓度依赖性。结论姜黄素通过抑制雄激素受体的表达减弱对PSA基因启动子的作用，从而抑制PSA的表达。     

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.The present work is part of a research project developed with a grant for the Plan Nacional de I + D (FAR 90-0092) of the Ministry of Industry and Energy of Spain.     

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR-dual activator in rats

Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats.