中药降香的质量控制和体内代谢研究
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摘要
本文以《中国药典》收载的豆科植物中药降香为研究对象，对其进行了质量控制和体内代谢方面的研究。
采用溶剂法和各种色谱分离技术，对降香的化学成分进行了较为系统的研究，从降香中分离得到27个化合物。利用各种化学方法和现代光谱技术鉴定了25个化合物的结构，其中包括24个黄酮类化合物和1个齐墩果酸类化合物，其中首次从降香中分离得到的化合物有10个。
建立了评价降香药材质量的液相色谱指纹图谱分析方法，测定了37批不同来源的降香药材的HPLC-UV指纹图谱，根据指纹图谱相似度分析结果，将降香药材分为三类；利用LC／ESI-MS技术及对照品对照的方法，分别对三类药材中的主要成分进行了定性分析，并比较了其化学组成上的异同，为降香药材质量评价提供了依据。
对降香药材进行了多指标成份定性定量分析：建立了分析降香中黄酮类成分的HPLC-DAD／ESI-MS~2方法，在60min的分析时间内可以在线分离鉴定降香中的23个黄酮类成分，包括6个异黄酮类成分(isoflavone)、6个新黄酮类成分(neoflavone)、4个二氢异黄酮类成分(isoflavanone)、3个二氢黄酮类成分(flavanone)、2个查尔酮类成分(chalcone)、1个二氢异黄酮醇(isoflavanonol)和1个紫檀烷(pterocarpan)，并进一步研究了不同类别黄酮类化合物在负离子ESI-MS／MS模式下的特征性裂解规律；建立了用于评价降香药材质量的HPLC-UV方法，采用不同的色谱条件，在275nm波长条件下定量分析了10个黄酮类成分，在350nm波长条件下定量分析了9个黄酮类成分，并成功的用于测定32批不同来源降香药材中黄酮类化合物的含量。本研究建立的分析方法简单、快速、准确，适于黄酮类化合物的快速检测、结构鉴定和定量分析，为降香药材的质量控制提供了科学依据。
初步探讨了大鼠灌胃降香总黄酮后的体内代谢情况。采用HPLC-UV和HPLC-MS技术，对大鼠灌胃降香总黄酮后血清、尿液和组织器官中的主要黄酮类成分进行了定性定量分析。通过对照品对照，在血清和尿液中分别指认了18个黄酮类成分，在给药后45min的肝、肾、肺、心、脾脏样品中分别指认了16、17、7、10和7个黄酮类成分。测定了4个指标成分(3R)-4′-methoxy-2′，3，7-trihydroxyisoflavanone(1)、vestitone(2)、formononetin(3)和sativanone(4)在不同时间点的血清和组织样本中的浓度，测定了2个指标成分(3R)-4′-methoxy-2′，3，7-trihydroxyisoflavanone(1)和vestitone(2)在不同时间段的尿样中的浓度，初步探讨了其药代动力学、组织分布和排泄规律。采用酶水解的方法，考察了大鼠灌胃降香总黄酮后体内代谢过程中药物可能存在的葡萄糖醛酸苷和硫酸酯等结合物形式。结果表明：绝大多数黄酮类成分在酶水解前后均可被检出，但水解后明显增加，说明其在体内存在原型和二相代谢产物两种形式；进一步研究发现，大鼠体内二相代谢反应以硫酸酯结合为主，葡萄糖醛酸苷结合不显著。通过对降香体内代谢的研究，为临床制定安全、有效、合理的用药方案提供了基础，为阐明降香药材的治疗机理、质量评价方法和进一步开发利用提供了依据。
本研究在中医药学理论和实践的指导下，将中药化学、分析化学、生药学、药理学、药代动力学等手段相结合，研究了中药降香的化学成分、质量评价标准以及体内代谢过程，为中药现代化做了有意义的探索。
The heartwood of Dalbergia odorifera T. Chen. (Leguminosae) is a traditional Chinese medicine, named as Jiangxiang in Pharmacopoeia of PRC. The chemical constituents of D. odorifera and its quality control method, as well as the metabolism of this medicinal herb were investigated in detail.The chemical constituents of D. odorifera were systematically studied and 27 compounds were purified by silica gel, sephadex LH-20 and ODS column chromatography. Utilizing chemical and spectroscopic methods (UV, IR, NMR, MS), the structures of 25 compounds were fully characterized, including 24 flavonoids and 1 oleanolic acid. Ten of these constituents were isolated from D. odorifera for the first time.The method of HPLC-fingerprint analysis was established for the quality control of D. odorifera. The 37 batches of D. odorifera samples were analyzed and classified into three types based on the results of similarity analysis. Furthermore, the typical samples were detected by LC/ESI-MS under the negative ion mode, and the main constituents of D. odorifera were identified. The method is repeatable and reliable, and proved to be able to effectively control the quality of D. odorifera.The major flavonoids in D. odorifera were analyzed qualitatively and quantitatively by high performance liquid chromatography and its coupling to mass Spectrometry. A HPLC-DAD/ESI-MS~2 method was developed for the qualitative characterization of flavonoids in D. odorifera. Twenty-three flavonoids including six isoflavones, six neoflavones, four isoflavanones, three flavanones, two chalcones, one isoflavanonol and one pterocarpan were unambiguously identified by comparing their retention times, UV and MS spectra with those of authentic compounds. Furthermore, the MS/MS spectra were studied by collision-induced dissociation (CID) from the [M-H]~- ions to clarify the mass spectrometric behavior of different types of flavonoids. HPLC-UV methods were developed for the simultaneous quantification of major flavonoids in D. odorifera: ten constituents were detected at 275 nm and nine were detected at 350 nm. The current assay methods were applied to 32 batches of samples and considered to be suitable for the quality control of Dalbergia odorifera samples.
The absorption, distribution, metabolism and extraction of flavonoids in rat after oral administration of D. odorifera extract were preliminarily investigated. The major flavonoids in rat serum, urine and tissues were analyzed qualitatively and quantitatively by high performance liquid chromatography and its coupling to mass spectrometry. Utilizing HPLC-MS technique, eighteen flavonoids including five isoflavones, four isoflavanones, four neoflavones, two flavanones, two chalcones, one isoflavanonol were detected in free form in serum and urine samples based on comparison with the authentic standards. Moreover, 16, 17, 7, 10 and 7 flavonoids were identified in free form in liver, kidney, lung, heart and spleen samples, respectively. Furthermore, the amounts of the four prominent flavonoids, (3R)-4'-methoxy-2',3,7-trihydroxyisoflavanone, vestitone, formononetin and sativanone were determined in serum and tissues by HPLC-UV with internal standard method; (3R)-4'-methoxy-2',3,7-trihydroxyisoflavanone and vestitone were determined in urine. The methods were validated and utilized in pharrnacokinetic studies, distribution in tissues and renal excretion of these analytes. The sulfate and glucuronide conjugates of the flavonoids in rat were studied by hydrolysis withβ-glucuronidase/sulfatase. Most of the flavonoids could be detected both before and after enzyme treatment, which suggested that the flavonoids were present in both free and conjugated forms in rat. Further studies showed that sulfation was the primary conjugation in rat, while glucuronidation was not remarkable. The investigation on the metabolism of D. odorifera extract provided a firm basis for clarifying the pharmacological effect of D. odorifera and evaluating the clinical applications of this medicinal herb.
Under the direction of theory and clinical practice of TCM, utilizing the knowledge of phytochemistry, pharmaceutical analysis, pharmacognosy, pharmacology and pharmacokinetics, the quality assessment methods for D. odorifera were developed, the metabolism of this medicinal herb was also investigated to some extend. This research provided a beneficial exploration for the modernization of traditional Chinese medicine.
采用溶剂法和各种色谱分离技术，对降香的化学成分进行了较为系统的研究，从降香中分离得到27个化合物。利用各种化学方法和现代光谱技术鉴定了25个化合物的结构，其中包括24个黄酮类化合物和1个齐墩果酸类化合物，其中首次从降香中分离得到的化合物有10个。
建立了评价降香药材质量的液相色谱指纹图谱分析方法，测定了37批不同来源的降香药材的HPLC-UV指纹图谱，根据指纹图谱相似度分析结果，将降香药材分为三类；利用LC／ESI-MS技术及对照品对照的方法，分别对三类药材中的主要成分进行了定性分析，并比较了其化学组成上的异同，为降香药材质量评价提供了依据。
对降香药材进行了多指标成份定性定量分析：建立了分析降香中黄酮类成分的HPLC-DAD／ESI-MS~2方法，在60min的分析时间内可以在线分离鉴定降香中的23个黄酮类成分，包括6个异黄酮类成分(isoflavone)、6个新黄酮类成分(neoflavone)、4个二氢异黄酮类成分(isoflavanone)、3个二氢黄酮类成分(flavanone)、2个查尔酮类成分(chalcone)、1个二氢异黄酮醇(isoflavanonol)和1个紫檀烷(pterocarpan)，并进一步研究了不同类别黄酮类化合物在负离子ESI-MS／MS模式下的特征性裂解规律；建立了用于评价降香药材质量的HPLC-UV方法，采用不同的色谱条件，在275nm波长条件下定量分析了10个黄酮类成分，在350nm波长条件下定量分析了9个黄酮类成分，并成功的用于测定32批不同来源降香药材中黄酮类化合物的含量。本研究建立的分析方法简单、快速、准确，适于黄酮类化合物的快速检测、结构鉴定和定量分析，为降香药材的质量控制提供了科学依据。
初步探讨了大鼠灌胃降香总黄酮后的体内代谢情况。采用HPLC-UV和HPLC-MS技术，对大鼠灌胃降香总黄酮后血清、尿液和组织器官中的主要黄酮类成分进行了定性定量分析。通过对照品对照，在血清和尿液中分别指认了18个黄酮类成分，在给药后45min的肝、肾、肺、心、脾脏样品中分别指认了16、17、7、10和7个黄酮类成分。测定了4个指标成分(3R)-4′-methoxy-2′，3，7-trihydroxyisoflavanone(1)、vestitone(2)、formononetin(3)和sativanone(4)在不同时间点的血清和组织样本中的浓度，测定了2个指标成分(3R)-4′-methoxy-2′，3，7-trihydroxyisoflavanone(1)和vestitone(2)在不同时间段的尿样中的浓度，初步探讨了其药代动力学、组织分布和排泄规律。采用酶水解的方法，考察了大鼠灌胃降香总黄酮后体内代谢过程中药物可能存在的葡萄糖醛酸苷和硫酸酯等结合物形式。结果表明：绝大多数黄酮类成分在酶水解前后均可被检出，但水解后明显增加，说明其在体内存在原型和二相代谢产物两种形式；进一步研究发现，大鼠体内二相代谢反应以硫酸酯结合为主，葡萄糖醛酸苷结合不显著。通过对降香体内代谢的研究，为临床制定安全、有效、合理的用药方案提供了基础，为阐明降香药材的治疗机理、质量评价方法和进一步开发利用提供了依据。
本研究在中医药学理论和实践的指导下，将中药化学、分析化学、生药学、药理学、药代动力学等手段相结合，研究了中药降香的化学成分、质量评价标准以及体内代谢过程，为中药现代化做了有意义的探索。
The heartwood of Dalbergia odorifera T. Chen. (Leguminosae) is a traditional Chinese medicine, named as Jiangxiang in Pharmacopoeia of PRC. The chemical constituents of D. odorifera and its quality control method, as well as the metabolism of this medicinal herb were investigated in detail.The chemical constituents of D. odorifera were systematically studied and 27 compounds were purified by silica gel, sephadex LH-20 and ODS column chromatography. Utilizing chemical and spectroscopic methods (UV, IR, NMR, MS), the structures of 25 compounds were fully characterized, including 24 flavonoids and 1 oleanolic acid. Ten of these constituents were isolated from D. odorifera for the first time.The method of HPLC-fingerprint analysis was established for the quality control of D. odorifera. The 37 batches of D. odorifera samples were analyzed and classified into three types based on the results of similarity analysis. Furthermore, the typical samples were detected by LC/ESI-MS under the negative ion mode, and the main constituents of D. odorifera were identified. The method is repeatable and reliable, and proved to be able to effectively control the quality of D. odorifera.The major flavonoids in D. odorifera were analyzed qualitatively and quantitatively by high performance liquid chromatography and its coupling to mass Spectrometry. A HPLC-DAD/ESI-MS~2 method was developed for the qualitative characterization of flavonoids in D. odorifera. Twenty-three flavonoids including six isoflavones, six neoflavones, four isoflavanones, three flavanones, two chalcones, one isoflavanonol and one pterocarpan were unambiguously identified by comparing their retention times, UV and MS spectra with those of authentic compounds. Furthermore, the MS/MS spectra were studied by collision-induced dissociation (CID) from the [M-H]~- ions to clarify the mass spectrometric behavior of different types of flavonoids. HPLC-UV methods were developed for the simultaneous quantification of major flavonoids in D. odorifera: ten constituents were detected at 275 nm and nine were detected at 350 nm. The current assay methods were applied to 32 batches of samples and considered to be suitable for the quality control of Dalbergia odorifera samples.
The absorption, distribution, metabolism and extraction of flavonoids in rat after oral administration of D. odorifera extract were preliminarily investigated. The major flavonoids in rat serum, urine and tissues were analyzed qualitatively and quantitatively by high performance liquid chromatography and its coupling to mass spectrometry. Utilizing HPLC-MS technique, eighteen flavonoids including five isoflavones, four isoflavanones, four neoflavones, two flavanones, two chalcones, one isoflavanonol were detected in free form in serum and urine samples based on comparison with the authentic standards. Moreover, 16, 17, 7, 10 and 7 flavonoids were identified in free form in liver, kidney, lung, heart and spleen samples, respectively. Furthermore, the amounts of the four prominent flavonoids, (3R)-4'-methoxy-2',3,7-trihydroxyisoflavanone, vestitone, formononetin and sativanone were determined in serum and tissues by HPLC-UV with internal standard method; (3R)-4'-methoxy-2',3,7-trihydroxyisoflavanone and vestitone were determined in urine. The methods were validated and utilized in pharrnacokinetic studies, distribution in tissues and renal excretion of these analytes. The sulfate and glucuronide conjugates of the flavonoids in rat were studied by hydrolysis withβ-glucuronidase/sulfatase. Most of the flavonoids could be detected both before and after enzyme treatment, which suggested that the flavonoids were present in both free and conjugated forms in rat. Further studies showed that sulfation was the primary conjugation in rat, while glucuronidation was not remarkable. The investigation on the metabolism of D. odorifera extract provided a firm basis for clarifying the pharmacological effect of D. odorifera and evaluating the clinical applications of this medicinal herb.
Under the direction of theory and clinical practice of TCM, utilizing the knowledge of phytochemistry, pharmaceutical analysis, pharmacognosy, pharmacology and pharmacokinetics, the quality assessment methods for D. odorifera were developed, the metabolism of this medicinal herb was also investigated to some extend. This research provided a beneficial exploration for the modernization of traditional Chinese medicine.
引文
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