硝唑尼特在山羊体内的药物代谢动力学及毒理学研究
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摘要
硝唑尼特(nitazoxanide, NTZ)是一种硝基噻唑苯胺类化合物,具有广谱抗微生物活性,对寄生虫,细菌以及病毒有效。体内活性与其脱乙酰基衍生物替唑尼特(tizoxanide, T)有关,具体包括细胞内外的原虫,蠕虫,需氧与厌氧菌,以及病毒。因此,进行硝唑尼特的药理学与毒理学研究将对其进一步开发及应用会产生重要的作用。
我们首先建立了一种用于山羊粪便中硝唑尼特代谢物鉴定的敏感、特异的液相色谱电喷雾串联质谱(liquid chromatography–electrospray ionization tandem mass spectrometry, LC–ESI–MS–MS)方法,并且采用了ESI阴离子模式。样品经前处理后注入XTerra MS C8柱,试验过程中使用的流动相为乙腈(acetonitrile)与10 mM乙酸铵(ammonium acetate),以0.2 ml/min的流速进行线性梯度洗脱(linear gradient elution),随后进行MS–MS检测。代谢物鉴定以及结构解析通过比较原药或其它可用标准的保留时间(retention times, Rt),全扫描,子离子扫描,母离子扫描与中性丢失扫描的MS–MS质谱图来完成。山羊按200 mg/kg的剂量经口给予硝唑尼特后,在其粪便中发现原药(nitazoxanide)及其脱乙酰基代谢物(替唑尼特,Tizoxanide)。给药96 h后,在山羊粪便中仍能检测到替唑尼特。
在上述方法的基础上,建立了一种用于山羊血浆及尿液中硝唑尼特代谢物鉴定的快速,敏感与特异的液相色谱–串联质谱方法。纯化的样品使用XTerra MS C8柱进行分离,流动相为乙腈与10 mM乙酸铵(pH 2.5),采用梯度洗脱的方式,样品检测使用MS–MS。代谢物鉴定以及结构解析通过比较原药或其它可用标准的保留时间(retention times, Rt),全扫描,子离子扫描,母离子扫描与中性丢失扫描的MS–MS质谱图来完成。山羊按200 mg/kg的剂量经口给予硝唑尼特后,在其血浆及尿液中发现并鉴定了四种代谢[替唑尼特(tizoxanide),替唑尼特葡萄糖醛酸化物(tizoxanide glucuronide),替唑尼特硫酸酯化物(tizoxanide sulfate)以及羟基替唑尼特硫酸酯化物(hydroxylated tizoxanide sulfate)]。此外,我们首次提出了硝唑尼特在山羊体内可能的代谢途径。研究结果提示,建立的该方法简单,可靠及敏感,证明适合于硝唑尼特活性代谢物的检测及其结构鉴定,从而有助于更好地理解硝唑尼特的体内代谢。
建立山羊血浆中测定硝唑尼活性代谢物替唑尼特的简单且特异的HPLC–UV方法。血浆样品用乙腈去蛋白提取,选用Diamonsil C18 (250 mm×4.6 mm, 5μm)为反相色谱柱,乙腈–0.02 mol/l KH2PO4(65:35, v/v)为流动相,流速1.0 ml/min,检测波长360 nm。替唑尼特线性范围为0.2–10μg/ml,检测限为0.02μg/ml (S/N>3),定量限为0.04μg/ml (S/N>6)。样品平均回收率在94.5%以上,日内、日间精密度的RSD均小于10%,准确率的相对误差在1.42到9.05%之间。其它物质干扰替唑尼特的检测。确证方法成功应用于山羊经口给予硝唑尼特后,其血浆中替唑尼特的药物动力学研究。
研究了硝唑尼特活性代谢物替唑尼特在山羊体内的药物代谢物动力学及其在山羊血浆、白蛋白(albumin)与α-1-酸-糖蛋白(α-1-acid-glycoprotein)溶液中的结合能力。使用HPLC–UV方法分析血浆及蛋白质结合样品,检测波长为360 nm,,采用3P97药物动力学程序软件处理药-时数据。山羊血浆中替唑尼特的浓度可以检测到24 h。按200 mg/kg的剂量经口给予山羊硝唑尼特胶囊后,其血浆中替唑尼特浓度–时间数据符合符合一室开放模型(one-compartment open model),并且存在一级吸收(first order absorption)。主要药动学参数分别为:t1/2Ka 2.51±0.41 h, t1/2Ke 3.47±0.32 h, Tmax 4.90±0.13 h, Cmax 2.56±0.25μg/ ml, AUC 27.40±1.54 (μg/ml)×h, V/F(c) 30.17±2.17 l/kg和CL(s) 7.34±1.21 l/(kg×h)。血浆样品β-葡萄糖苷酸酶(β-glucuronidase)酶解后,t1/2ke, Cmax, Tmax, AUC增加,而V/F(c)与CL(s)却减小。体外蛋白质结合能力研究结果表明,4μg/ml的替唑尼特在山羊血浆与白蛋白(albumin)溶液中的结合率可达95%以上,而在α-1-酸-糖蛋白溶液中的结合率仅为49%。这一结果表明,替唑尼特以其酸性特征,同α-1-酸-糖蛋白相比,可能与白蛋白具有较强的结合能力。
最后,进行了硝唑尼特体内外毒理学以及潜在作用机制的研究。按照200 mg/kg的剂量给口给予山羊硝唑尼特。通过11项尿常规分析与心脏,肝脏,脾脏,肺脏,肾脏,膀胱及胆囊的组织学检查评价了硝唑尼特的系统毒性。结果证实,硝唑尼特无毒,尿常规分析的11项指标正常,而且无器官组织病变出现。MTT试验证实,低于10μg/ml的硝唑尼特对Chang氏肝细胞与Vero细胞的生长无影响,而对两种细胞的敏感性不同。然而,当浓度为10~100μg/ml时,对两种细胞的生长均有量效相关的抑制作用,且对Chang氏肝细胞与Vero细胞的IC50分别为37μg/ml与41μg/ml。同空白细胞对照相比,药物处理特别是较高剂量的硝唑尼特作用可以使293T细胞数量减少,皱缩明显,凋亡增多。用Western blot进一步分析,结果发现,硝唑尼特可以促进p53表达,且作用剂量为10μg/ml时不影响细胞周期。总之,硝唑尼特具有良好的耐受性,而且能促进p53表达,从而导致细胞凋亡。
Nitazoxanide is a nitrothiazole benzamide compound that has a wide range of antimicrobial activity against parasites, bacterial, viral pathogens. The broad spectrum of in vivo activity is related to its desacetyl derivative, tizoxanide, and includes intracellular and extracellular protozoa, helminthes, aerobic and anaerobic bacteria, and virus. Therefore, the investigations on pharmacology and toxicology of nitazoxanide play an important role in its further development and application.
A sensitive and specific method for the identification of nitazoxanide metabolites in goat feces by liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI–MS–MS) with negative ion mode was firstly developed. After extraction procedure the pretreated samples were injected on an XTerra MS C8 column with mobile phase (0.2 ml/min) of acetonitrile and 10 mM ammonium acetate (adjusted to pH 2.5 with formic acid) followed a linear gradient elution, and detected by MS–MS. Identification and structural elucidation of the metabolites were performed by comparing their retention times (Rt), full scan, product ion scan, precursor ion scan and neutral loss scan MS–MS spectra with those of the parent drug or other available standard. The parent drug (nitazoxanide) and its deacetyl metabolite (tizoxanide) were found in goat feces after the administration of a single oral dose of 200 mg/kg of nitazoxanide. Tizoxanide was detected in goat feces for up 96 h after ingestion of nitazoxanide.
According to the method described above, a rapid, sensitive and specific liquid chromatography–electrospray ionization (ESI) tandem mass spectrometry (LC–MS–MS) method has been developed for the identification of nitazoxanide metabolites in goat plasma and urine. The purified samples was separated using an XTerra MS C8 column with the mobile phase consisted of acetonitirle and 10 mM ammonium acetate buffer (pH 2.5) followed a linear gradient elution, and detected by MS–MS. Identification and structural elucidation of the metabolites were performed by comparing their retention-times, full scan, product ion scan, precursor ion scan and neutral loss scan MS–MS spectra with those of the parent drug or other available standard. Four metabolites (tizoxanide, tizoxanide glucuronide, tizoxanide sulfate and hydroxylated tizoxanide sulfate) were found and identified in goat after single oral administration of 200 mg/kg dose of nitazoxanide. In addition, the possible metabolic pathway was proposed for the first time. The results proved that the established method was simple, reliable and sensitive, revealing that it could be used to rapid screen and identify the structures of active metabolites responsible for pharmacological effects of nitazoxanide and to better understand its in vivo metabolism.
A simple and specific high-performance liquid chromatographic (HPLC) method with ultraviolet (UV) absorbance detection has been developed for the determination of tizoxanide, the active metabolite of nitazoxanide, in goat plasma. The plasma samples were deproteinized with acetonitrile. The analysis was performed on a Diamonsil C18 reversed-phase column (250 mm×4.6 mm, 5μm) with acetonitrile– 0.02 mol/l KH2PO4 (65:35, v/v) as mobile phase at a flow rate of 1.0 ml/min over 10 min. Detection wavelength was set at 360 nm. The linear range was 0.2–10μg/ml, the limit of detection (LOD) and the limit of quantification was 0.02 and 0.04μg/ml, respectively. The intra- and inter-day coefficient of variation (CV%) were less than 10%, respectively, and accuracy as relative error (RE%) between 1.42 and 9.05%. Mean extraction recovery was above 94.5%. There was no interference of sources on the determination of tizoxanide. The validated method was successfully applied to the pharmacokinetic study of tizoxanide in goat plasma after oral administration of nitazoxanide capsules at a dose of 100 mg/kg.
The pharmacokinetics of nitazoxanide, in form of its active metabolite, tizoxanide, and its to its protein binding ability in goat plasma and in the solutions of albumin andα-1-acid-glycoprotein were investigated. The plasma and protein binding samples were analyzed using a high-performance liquid chromatography (HPLC) assay with UV detection at 360 nm. The plasma concentration of tizoxanide were detectable in goats up to 24 h. Plasma concentrations versus time data of tizoxanide after 200 mg/kg oral administration of nitazoxanide in goats were adequately described by one-compartment open model with first order absorption. The values of t1/2Ka, t1/2Ke, Tmax, Cmax, AUC, V/F(c) and CL(s) were 2.51±0.41 h, 3.47±0.32 h, 4.90±0.13 h, 2.56±0.25μg/ml, 27.40±1.54 (μg/ml)×h, 30.17±2.17 l/kg and 7.34±1.21 l/(kg×h), respectively. Afterβ-glucuronidase hydrolysis, t1/2ke, Cmax, Tmax, AUC increased, while the V/F(c) and CL(s) decreased. Study of the protein binding ability showed that tizoxanide with 4μg/ml concentration in goat plasma and in the albumin solution achieved a protein binding rate of more than 95%, while in the solution ofα-1-acid-glycoprotein the rate was only about 49%. This result suggested that tizoxanide might have much more potent binding ability with albumin than withα-1-acid-glycoprotein, since its acidic property.
Finally, the toxicological effects of nitazoxanide in vivo and in vitro, as well as its potential mechanism were were investigated. Single oral gavage doses of 200 mg per kg body weight were administered to goats. Systemic toxicity was evaluated with urine routine analysis including 11 indexes and Histology examination including heart, liver, spleen, lung, kidney, urinary bladder and gall bladder evaluation. Nitazoxanide has been shown to be nontoxic, with no abnormalities in urine routine analysis as well as gross and histopathological examination of animals. The cytotoxicity results from MTT assay demonstrated nitazoxanide at concentrations of under 10μg/ml with no obvious effects on the growth of cells, show different sensitivity to Chang liver cells and Vero cells. However, nitazoxanide at concentrations of 10~100μg/ml can inhibit the cell growth in a dose-dependent manner, and IC50 for Chang liver cells and Vero cells were 37μg/ml and 41μg/ml, respectively. Compared with control group, the 293T cells treated with nitazoxanide especially more than 10μg/ml show quantitatively reduced, abnormal or wizened morphology, and the number of apoptosis cells was increased. Futher analysis with Western blot was carried out, and results showed that nitazoxanide could enhance the expression of p53, although not significantly, and did not affect cell cycle (10μg/ml). This study demonstrated that nitazoxanide appears to be well tolerated, and could enhance p53 expression to a certain extent, and thus induce apoptosis.
我们首先建立了一种用于山羊粪便中硝唑尼特代谢物鉴定的敏感、特异的液相色谱电喷雾串联质谱(liquid chromatography–electrospray ionization tandem mass spectrometry, LC–ESI–MS–MS)方法,并且采用了ESI阴离子模式。样品经前处理后注入XTerra MS C8柱,试验过程中使用的流动相为乙腈(acetonitrile)与10 mM乙酸铵(ammonium acetate),以0.2 ml/min的流速进行线性梯度洗脱(linear gradient elution),随后进行MS–MS检测。代谢物鉴定以及结构解析通过比较原药或其它可用标准的保留时间(retention times, Rt),全扫描,子离子扫描,母离子扫描与中性丢失扫描的MS–MS质谱图来完成。山羊按200 mg/kg的剂量经口给予硝唑尼特后,在其粪便中发现原药(nitazoxanide)及其脱乙酰基代谢物(替唑尼特,Tizoxanide)。给药96 h后,在山羊粪便中仍能检测到替唑尼特。
在上述方法的基础上,建立了一种用于山羊血浆及尿液中硝唑尼特代谢物鉴定的快速,敏感与特异的液相色谱–串联质谱方法。纯化的样品使用XTerra MS C8柱进行分离,流动相为乙腈与10 mM乙酸铵(pH 2.5),采用梯度洗脱的方式,样品检测使用MS–MS。代谢物鉴定以及结构解析通过比较原药或其它可用标准的保留时间(retention times, Rt),全扫描,子离子扫描,母离子扫描与中性丢失扫描的MS–MS质谱图来完成。山羊按200 mg/kg的剂量经口给予硝唑尼特后,在其血浆及尿液中发现并鉴定了四种代谢[替唑尼特(tizoxanide),替唑尼特葡萄糖醛酸化物(tizoxanide glucuronide),替唑尼特硫酸酯化物(tizoxanide sulfate)以及羟基替唑尼特硫酸酯化物(hydroxylated tizoxanide sulfate)]。此外,我们首次提出了硝唑尼特在山羊体内可能的代谢途径。研究结果提示,建立的该方法简单,可靠及敏感,证明适合于硝唑尼特活性代谢物的检测及其结构鉴定,从而有助于更好地理解硝唑尼特的体内代谢。
建立山羊血浆中测定硝唑尼活性代谢物替唑尼特的简单且特异的HPLC–UV方法。血浆样品用乙腈去蛋白提取,选用Diamonsil C18 (250 mm×4.6 mm, 5μm)为反相色谱柱,乙腈–0.02 mol/l KH2PO4(65:35, v/v)为流动相,流速1.0 ml/min,检测波长360 nm。替唑尼特线性范围为0.2–10μg/ml,检测限为0.02μg/ml (S/N>3),定量限为0.04μg/ml (S/N>6)。样品平均回收率在94.5%以上,日内、日间精密度的RSD均小于10%,准确率的相对误差在1.42到9.05%之间。其它物质干扰替唑尼特的检测。确证方法成功应用于山羊经口给予硝唑尼特后,其血浆中替唑尼特的药物动力学研究。
研究了硝唑尼特活性代谢物替唑尼特在山羊体内的药物代谢物动力学及其在山羊血浆、白蛋白(albumin)与α-1-酸-糖蛋白(α-1-acid-glycoprotein)溶液中的结合能力。使用HPLC–UV方法分析血浆及蛋白质结合样品,检测波长为360 nm,,采用3P97药物动力学程序软件处理药-时数据。山羊血浆中替唑尼特的浓度可以检测到24 h。按200 mg/kg的剂量经口给予山羊硝唑尼特胶囊后,其血浆中替唑尼特浓度–时间数据符合符合一室开放模型(one-compartment open model),并且存在一级吸收(first order absorption)。主要药动学参数分别为:t1/2Ka 2.51±0.41 h, t1/2Ke 3.47±0.32 h, Tmax 4.90±0.13 h, Cmax 2.56±0.25μg/ ml, AUC 27.40±1.54 (μg/ml)×h, V/F(c) 30.17±2.17 l/kg和CL(s) 7.34±1.21 l/(kg×h)。血浆样品β-葡萄糖苷酸酶(β-glucuronidase)酶解后,t1/2ke, Cmax, Tmax, AUC增加,而V/F(c)与CL(s)却减小。体外蛋白质结合能力研究结果表明,4μg/ml的替唑尼特在山羊血浆与白蛋白(albumin)溶液中的结合率可达95%以上,而在α-1-酸-糖蛋白溶液中的结合率仅为49%。这一结果表明,替唑尼特以其酸性特征,同α-1-酸-糖蛋白相比,可能与白蛋白具有较强的结合能力。
最后,进行了硝唑尼特体内外毒理学以及潜在作用机制的研究。按照200 mg/kg的剂量给口给予山羊硝唑尼特。通过11项尿常规分析与心脏,肝脏,脾脏,肺脏,肾脏,膀胱及胆囊的组织学检查评价了硝唑尼特的系统毒性。结果证实,硝唑尼特无毒,尿常规分析的11项指标正常,而且无器官组织病变出现。MTT试验证实,低于10μg/ml的硝唑尼特对Chang氏肝细胞与Vero细胞的生长无影响,而对两种细胞的敏感性不同。然而,当浓度为10~100μg/ml时,对两种细胞的生长均有量效相关的抑制作用,且对Chang氏肝细胞与Vero细胞的IC50分别为37μg/ml与41μg/ml。同空白细胞对照相比,药物处理特别是较高剂量的硝唑尼特作用可以使293T细胞数量减少,皱缩明显,凋亡增多。用Western blot进一步分析,结果发现,硝唑尼特可以促进p53表达,且作用剂量为10μg/ml时不影响细胞周期。总之,硝唑尼特具有良好的耐受性,而且能促进p53表达,从而导致细胞凋亡。
Nitazoxanide is a nitrothiazole benzamide compound that has a wide range of antimicrobial activity against parasites, bacterial, viral pathogens. The broad spectrum of in vivo activity is related to its desacetyl derivative, tizoxanide, and includes intracellular and extracellular protozoa, helminthes, aerobic and anaerobic bacteria, and virus. Therefore, the investigations on pharmacology and toxicology of nitazoxanide play an important role in its further development and application.
A sensitive and specific method for the identification of nitazoxanide metabolites in goat feces by liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI–MS–MS) with negative ion mode was firstly developed. After extraction procedure the pretreated samples were injected on an XTerra MS C8 column with mobile phase (0.2 ml/min) of acetonitrile and 10 mM ammonium acetate (adjusted to pH 2.5 with formic acid) followed a linear gradient elution, and detected by MS–MS. Identification and structural elucidation of the metabolites were performed by comparing their retention times (Rt), full scan, product ion scan, precursor ion scan and neutral loss scan MS–MS spectra with those of the parent drug or other available standard. The parent drug (nitazoxanide) and its deacetyl metabolite (tizoxanide) were found in goat feces after the administration of a single oral dose of 200 mg/kg of nitazoxanide. Tizoxanide was detected in goat feces for up 96 h after ingestion of nitazoxanide.
According to the method described above, a rapid, sensitive and specific liquid chromatography–electrospray ionization (ESI) tandem mass spectrometry (LC–MS–MS) method has been developed for the identification of nitazoxanide metabolites in goat plasma and urine. The purified samples was separated using an XTerra MS C8 column with the mobile phase consisted of acetonitirle and 10 mM ammonium acetate buffer (pH 2.5) followed a linear gradient elution, and detected by MS–MS. Identification and structural elucidation of the metabolites were performed by comparing their retention-times, full scan, product ion scan, precursor ion scan and neutral loss scan MS–MS spectra with those of the parent drug or other available standard. Four metabolites (tizoxanide, tizoxanide glucuronide, tizoxanide sulfate and hydroxylated tizoxanide sulfate) were found and identified in goat after single oral administration of 200 mg/kg dose of nitazoxanide. In addition, the possible metabolic pathway was proposed for the first time. The results proved that the established method was simple, reliable and sensitive, revealing that it could be used to rapid screen and identify the structures of active metabolites responsible for pharmacological effects of nitazoxanide and to better understand its in vivo metabolism.
A simple and specific high-performance liquid chromatographic (HPLC) method with ultraviolet (UV) absorbance detection has been developed for the determination of tizoxanide, the active metabolite of nitazoxanide, in goat plasma. The plasma samples were deproteinized with acetonitrile. The analysis was performed on a Diamonsil C18 reversed-phase column (250 mm×4.6 mm, 5μm) with acetonitrile– 0.02 mol/l KH2PO4 (65:35, v/v) as mobile phase at a flow rate of 1.0 ml/min over 10 min. Detection wavelength was set at 360 nm. The linear range was 0.2–10μg/ml, the limit of detection (LOD) and the limit of quantification was 0.02 and 0.04μg/ml, respectively. The intra- and inter-day coefficient of variation (CV%) were less than 10%, respectively, and accuracy as relative error (RE%) between 1.42 and 9.05%. Mean extraction recovery was above 94.5%. There was no interference of sources on the determination of tizoxanide. The validated method was successfully applied to the pharmacokinetic study of tizoxanide in goat plasma after oral administration of nitazoxanide capsules at a dose of 100 mg/kg.
The pharmacokinetics of nitazoxanide, in form of its active metabolite, tizoxanide, and its to its protein binding ability in goat plasma and in the solutions of albumin andα-1-acid-glycoprotein were investigated. The plasma and protein binding samples were analyzed using a high-performance liquid chromatography (HPLC) assay with UV detection at 360 nm. The plasma concentration of tizoxanide were detectable in goats up to 24 h. Plasma concentrations versus time data of tizoxanide after 200 mg/kg oral administration of nitazoxanide in goats were adequately described by one-compartment open model with first order absorption. The values of t1/2Ka, t1/2Ke, Tmax, Cmax, AUC, V/F(c) and CL(s) were 2.51±0.41 h, 3.47±0.32 h, 4.90±0.13 h, 2.56±0.25μg/ml, 27.40±1.54 (μg/ml)×h, 30.17±2.17 l/kg and 7.34±1.21 l/(kg×h), respectively. Afterβ-glucuronidase hydrolysis, t1/2ke, Cmax, Tmax, AUC increased, while the V/F(c) and CL(s) decreased. Study of the protein binding ability showed that tizoxanide with 4μg/ml concentration in goat plasma and in the albumin solution achieved a protein binding rate of more than 95%, while in the solution ofα-1-acid-glycoprotein the rate was only about 49%. This result suggested that tizoxanide might have much more potent binding ability with albumin than withα-1-acid-glycoprotein, since its acidic property.
Finally, the toxicological effects of nitazoxanide in vivo and in vitro, as well as its potential mechanism were were investigated. Single oral gavage doses of 200 mg per kg body weight were administered to goats. Systemic toxicity was evaluated with urine routine analysis including 11 indexes and Histology examination including heart, liver, spleen, lung, kidney, urinary bladder and gall bladder evaluation. Nitazoxanide has been shown to be nontoxic, with no abnormalities in urine routine analysis as well as gross and histopathological examination of animals. The cytotoxicity results from MTT assay demonstrated nitazoxanide at concentrations of under 10μg/ml with no obvious effects on the growth of cells, show different sensitivity to Chang liver cells and Vero cells. However, nitazoxanide at concentrations of 10~100μg/ml can inhibit the cell growth in a dose-dependent manner, and IC50 for Chang liver cells and Vero cells were 37μg/ml and 41μg/ml, respectively. Compared with control group, the 293T cells treated with nitazoxanide especially more than 10μg/ml show quantitatively reduced, abnormal or wizened morphology, and the number of apoptosis cells was increased. Futher analysis with Western blot was carried out, and results showed that nitazoxanide could enhance the expression of p53, although not significantly, and did not affect cell cycle (10μg/ml). This study demonstrated that nitazoxanide appears to be well tolerated, and could enhance p53 expression to a certain extent, and thus induce apoptosis.
引文
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