银杏酸（C17：1）的药物代谢和动力学研究
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摘要
银杏作为公认的预防和治疗心脑血管疾病的药物,在世界范围内有着极为广泛的应用。银杏酸(Ginkgolic Acids,简称GAs)是存在于银杏叶、果和外种皮中的生物活性成分,以外种皮中的含量最高。银杏酸是一类水杨酸衍生物,苯环6位上的侧链碳原子数为13至19个,侧链双键数为0至3个。其中银杏酸(C15：1,GA2)和(C17：1,GA5)是主要的化学成分,其含量约占到银杏酸总量的80%。银杏酸被认为是引起银杏制剂不良反应的主要原因,可引起细胞毒性、致敏、致突变、致癌、肝毒性和肾毒性等。另一方面,随着研究的深入发现银杏酸也具有广泛的药理活性,包括抗菌、抗炎、抗过敏、杀虫等作用,体外和体内对多种肿瘤细胞显示不同程度的抑制生长作用,对HIV病毒也有很好的抑制效果。关于银杏酸的研究多集中在药理和毒理方面,药物代谢及其动力学(DM/PK)的研究报道甚少。本研究在先期GA(C15：1)工作的的基础上,从银杏酸总酸提取物中分离、制备GA(C15：1)和GA(C17：1),进而采用各种体内外模型对GA(C17：1)的吸收、转运、代谢、排泄与动力学的性质进行了较系统的研究。本文的研究结果可为银杏酸的进一步开发提供理论和实验依据。
1.GA(C17：1)在大鼠肝微粒体中的代谢研究
GA(C17：1)可由CYPs酶介导发生Ⅰ相氧化代谢,UGTs介导发生Ⅱ相代谢。化学抑制剂实验表明,大鼠肝微粒体的CYP1A1/2和CYP3A是介导GA(C17:1)I相代谢的主要酶亚型,UGT1A7和UGT1A9为介导GA(C17:1)Ⅱ相代谢的酶亚型。GA(C17：1)对CYP1A1/2、CYP2D1、CYP2E1和CYP3A2没有抑制作用,对CYP2C6有中等程度的抑制作用(Ki=5.26±1.07μmol/L)。使用LC/MS-MS初步分析了GA(C17：1)在大鼠肝微粒体中的代谢物,GA(C17：1)经大鼠肝药酶代谢可发生羟基化和葡萄糖醛酸结合反应,生成三种代谢物(两个羟基化代谢物和一个葡萄糖醛酸结合代谢物)。
2.GA(C17：1)在人肝微粒体和人重组酶中的代谢研究
通过人肝微粒体中代谢研究发现,GA(C17：1)与人肝微粒体的亲和力小于大鼠肝微粒体。在人肝微粒体和重组酶中,CYP3A4和CYP1A2是介导GA(C17：1)代谢的两种CYPs酶亚型,UGT1A6、UGT1A9和UGT2B15是介导GA(C17：1)葡萄糖醛酸结合的主要亚型。GA(C17：1)对CYP2C9有中等程度的抑制作用。报告基因法显示,10μmol/L的GA(C17：1)对CYP2B6和CYP3A4基本没有诱导作用(<30%利福平诱导能力),对UGT1A1基因诱导作用存在浓度依赖性。
3.GA(C17：1)在HepG2、大鼠原代肝细胞和L02细胞上的代谢和毒性研究
GA(C17：1)对不同类型的肝细胞HepG2、大鼠原代肝细胞和L02细胞均存在一定程度的毒性。CYP酶的化学诱导剂β-萘黄酮和利福平能够降低HepG2细胞和大鼠原代肝细胞的存活率；CYP酶的化学抑制剂α-萘黄酮和酮康唑能够增加原代肝细胞的存活率。与大鼠原代肝细胞和L02细胞相比,GA(C17：1)对HepG2有更大的细胞毒性作用,并且I相代谢酶CYP1A和CYP3A能够通过生物转化使GA(C17：1)的毒性增加。
4.GA(C17：1)和GA(C15：1)在MDRl和BCRP转基因细胞模型上的转运研究
采用MDCK-MDR1和LLC-PK1-BCRP转基因细胞模型,研究了GA(C17：1)和GA(C15：1)的转运机制以及对P-gp功能的影响。结果表明,GA(C17：1)和GA(C15：1)均为外排转运体P-gp和BCRP的底物,提示GA(C17：1)和GA(C15：1)的口服生物利用度有限,并难以透过血脑屏障进入脑部。GA(C17：1)和GA(C15：1)对P-gp的外排功能也有一定的抑制作用。
5.GA(C17：1)在大鼠体内的药物动力学,组织分布和排泄研究
建立了测定大鼠体内生物样品中GA(C17：1)的LC-MS/MS法,该方法具有操作简便、灵敏度高、稳定性、重复性好等优点。药物动力学研究表明：GA(C17：1)吸收较快,生物利用度为19.5%,GA(C17：1)在大鼠体内分布广泛,在肝脏和肾脏中浓度较高,并难以透过血脑屏障,粪便排泄是其主要的排泄途径。在粪便中鉴定了两个GA(C17：1)的代谢产物。
6.银杏酸提取物在大鼠体内的药物动力学研究
建立了同时测定血浆中GA(C17：1)和GA(C15：1)的快速、准确、高灵敏LC-MS/MS法,并将此方法成功应用于银杏酸提取物在大鼠体内的药物动力学研究。结果表明,与银杏酸单体给药相比,GA(C17：1)和GA(C15：1)的药动学参数有了一定程度的改变。大鼠静脉给予P-gp和BCRP抑制剂CsA可以显著提高GA(C17：1)和GA(C15：1)血药浓度水平。此外,CsA还可以通过抑制脑中P-gp,增加GA(C17：1)和GA(C15：1)在脑中的分布。
Ginkgo biloba was widely used in the world as a drug for the prevention and treatment of cerebrovascular disease. Ginkgolic acid is a mixture of structurally related n-alkyl phenolic acid compounds and widely exists in leaves, nuts and external seed coat of Ginkgo biloba L. The alkyl side chain in molecular structures varies from13to19carbons in length with0-3double bonds. GA (C15:1) and GA (C17:1) are the two main ingredients accounted for nearly80%of the total ginkgolic acid. Ginkgolic acid is considered to be the toxic components of ginkgo with cytotoxicity, sensitization, mutagenic and carcinogenic, hepatotoxcity and nephrotoxicity. However, it was also reported that ginkgo acid has shown a wide range of pharmacological activities, including anti-bacterial, anti-inflammatory, anti-allergic, insecticidal, inhibition of the growth of a variety of tumor cells in vitro and in vivo as well as HIV protease activity and HIV infection in vitro. Most of the research focused on the pharmacological and toxicological aspects of ginkgolic acid, the reports about drug metabolism and pharmacokinetics of GAs are still rare. In this study, GA(C17:1) and GA(C15:1) were isolated and purified from the ginkgolic acid extract and their absorption, transport, metabolism, excretion and pharmacokinetics profiles were investigated by using several in vitro and in vivo models. The results of this study could provide theoretical and experimental basis for the further research of ginkgolic acid.
1. Metabolism of GA (C17:1) in rat liver microsomes
GA (C17:1) could be metabolized by CYPs (Phase I metabolism), and UGTs (Phase II metabolism). The special chemical inhibitor experiments indicated that CYP1A1/2and CYP3A were involved in GA (C17:1) oxidative metabolism; UGT1A7and UGT1A9were involved in GA (C17:1) glucuronidation metabolism. Classical CYPs' substrates were used to investigate the inhibition effect of GA (C17:1) on the CYPs, with the results that GA (C17:1) has inhibition effect on CYP2C6and no effect on CYP3A, CYP1A1/2, CYP2E1, CYP2D1. Three metabolites of GA (C17:1) in rat liver microsomes (RLMs) were analyzedas (two mono-hydroxylation metabolites and a glucuronidation metabolite) by LC-MS/MS.
2. Metabolism of GA (C17:1) in human liver microsomes, recombinant human CYPs and UGTs
The affinity of GA (C17:1) to human liver microsomes (HLMs) was less than that to RLMs. It was found that CYP3A4and CYP1A2were the two CYP enzyme isoforms that mediated the oxidative metabolism of GA (C17:1), UGT1A6, UGT1A9and UGT2B15were involved in GA (C17:1) glucuronidation metabolism. GA (C17:1) showed certain inhibition effect on CYP2C9. GA (C17:1) at10μmol/L showed no gene induction of CYP2B6and CYP3A4(<30%of rifampicin induction ability), concentration-dependent inductionof UGT1A1tested by dual-luciferase reporter assay.
3. The metabolism and toxicity of GA(C17:1) on HepG2, rat primary hepatocytes and L02cell
GA (C17:1) showed the different levels of toxicity on HepG2, rat primary hepatocytes and L02cell. Pretreatment with selective CYP inducers β-naphthoflavone and rifampin, could increase the cytotoxicity of ginkgolic acid (C17:1) in HepG2cells and rat primary hepatocytes. Co-incubation with selective CYP inhibitors a-naphthoflavone and ketoconazole could decrease the cytotoxicity of ginkgolic acid in primary rat hepatocytes. The results indicated that GA (C17:1) showed greater cytotoxicity on HepG2cells comparing with primary rat hepatocytes and L02cell, and CYP1A and3A catalyzed GA (C17:1) to more toxic metabolite.
4. Transport and uptake studies of GA (C17:1) and GA (C1S:1) in MDR1and BCRP transgenic cells
MDCK-MDR1and LLC-PK1-BCRP cells were adopted as the in vitro model to predict the intestinal absorption and blood-brain barrier (BBB) permeability. The results showed that GA (C17:1) and GA (C15:1) are the substrates of efflux transporters, P-gp and BCRP. GA (C17:1) and GA (C15:1) may have not very good oral bioavailability and BBB permeability. GA (C17:1) and GA (C15:1) had significant inhibition effects on the P-gp-mediated transport of R123across the MDCK-MDR1cell monolayer.
5. Plasma pharmacokinetics, tissue distribution, metabolism and excretion studies of ginkgolic acid (C17:1) in rats
A rapid and sensitive method for the determination of ginkgolic acid (C17:1) in rat biological samples was developed using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The pharmacokinetic investigation demonstrated that GA (C17:1) was rapidly absorbed with an absolute bioavailability being approximate19.5%. The tissue distribution indicated that liver and kidney were the major accumulation tissues for GA (C17:1) in rats. In addition, GA (C17:1) could hardly cross the blood-brain barrier. The excretion study suggested that feces was the main excretion pathway,while high proportion of GA (C17:1)(>35%) was excreted as the unchanged form. And two metabolites in feces were identified.
6. Pharmacokinetics of ginkgolic acid (C15:1) and ginkgolic acid (C17:1) in extract of external seed coat of ginkgo biloba L. in rat
A rapid and sensitive LC-MS/MS method for the simultaneous determination of ginkgolic aicd (C15:1) and ginkgolic aicd (C17:1) in rat plasma was developed and applied to investigate the pharmacokinetics of ginkgolic acid extract in rats. Compared with ginkgo acid monomers, the pharmacokinetic parameters of GA (C17:1) and GA (C15:1) has changed externally. Coadministrated intravenously P-gp and BCRP inhibitor CsA at20mg/kg can significantly improve GA (C17:1) and GA (C15:1) plasma concentration levels, CsA can also inhibit brain P-gp and BCRP, increased GA (C17:1) and GA (C15:1) distribution to the brain.
1.GA(C17：1)在大鼠肝微粒体中的代谢研究
GA(C17：1)可由CYPs酶介导发生Ⅰ相氧化代谢,UGTs介导发生Ⅱ相代谢。化学抑制剂实验表明,大鼠肝微粒体的CYP1A1/2和CYP3A是介导GA(C17:1)I相代谢的主要酶亚型,UGT1A7和UGT1A9为介导GA(C17:1)Ⅱ相代谢的酶亚型。GA(C17：1)对CYP1A1/2、CYP2D1、CYP2E1和CYP3A2没有抑制作用,对CYP2C6有中等程度的抑制作用(Ki=5.26±1.07μmol/L)。使用LC/MS-MS初步分析了GA(C17：1)在大鼠肝微粒体中的代谢物,GA(C17：1)经大鼠肝药酶代谢可发生羟基化和葡萄糖醛酸结合反应,生成三种代谢物(两个羟基化代谢物和一个葡萄糖醛酸结合代谢物)。
2.GA(C17：1)在人肝微粒体和人重组酶中的代谢研究
通过人肝微粒体中代谢研究发现,GA(C17：1)与人肝微粒体的亲和力小于大鼠肝微粒体。在人肝微粒体和重组酶中,CYP3A4和CYP1A2是介导GA(C17：1)代谢的两种CYPs酶亚型,UGT1A6、UGT1A9和UGT2B15是介导GA(C17：1)葡萄糖醛酸结合的主要亚型。GA(C17：1)对CYP2C9有中等程度的抑制作用。报告基因法显示,10μmol/L的GA(C17：1)对CYP2B6和CYP3A4基本没有诱导作用(<30%利福平诱导能力),对UGT1A1基因诱导作用存在浓度依赖性。
3.GA(C17：1)在HepG2、大鼠原代肝细胞和L02细胞上的代谢和毒性研究
GA(C17：1)对不同类型的肝细胞HepG2、大鼠原代肝细胞和L02细胞均存在一定程度的毒性。CYP酶的化学诱导剂β-萘黄酮和利福平能够降低HepG2细胞和大鼠原代肝细胞的存活率；CYP酶的化学抑制剂α-萘黄酮和酮康唑能够增加原代肝细胞的存活率。与大鼠原代肝细胞和L02细胞相比,GA(C17：1)对HepG2有更大的细胞毒性作用,并且I相代谢酶CYP1A和CYP3A能够通过生物转化使GA(C17：1)的毒性增加。
4.GA(C17：1)和GA(C15：1)在MDRl和BCRP转基因细胞模型上的转运研究
采用MDCK-MDR1和LLC-PK1-BCRP转基因细胞模型,研究了GA(C17：1)和GA(C15：1)的转运机制以及对P-gp功能的影响。结果表明,GA(C17：1)和GA(C15：1)均为外排转运体P-gp和BCRP的底物,提示GA(C17：1)和GA(C15：1)的口服生物利用度有限,并难以透过血脑屏障进入脑部。GA(C17：1)和GA(C15：1)对P-gp的外排功能也有一定的抑制作用。
5.GA(C17：1)在大鼠体内的药物动力学,组织分布和排泄研究
建立了测定大鼠体内生物样品中GA(C17：1)的LC-MS/MS法,该方法具有操作简便、灵敏度高、稳定性、重复性好等优点。药物动力学研究表明：GA(C17：1)吸收较快,生物利用度为19.5%,GA(C17：1)在大鼠体内分布广泛,在肝脏和肾脏中浓度较高,并难以透过血脑屏障,粪便排泄是其主要的排泄途径。在粪便中鉴定了两个GA(C17：1)的代谢产物。
6.银杏酸提取物在大鼠体内的药物动力学研究
建立了同时测定血浆中GA(C17：1)和GA(C15：1)的快速、准确、高灵敏LC-MS/MS法,并将此方法成功应用于银杏酸提取物在大鼠体内的药物动力学研究。结果表明,与银杏酸单体给药相比,GA(C17：1)和GA(C15：1)的药动学参数有了一定程度的改变。大鼠静脉给予P-gp和BCRP抑制剂CsA可以显著提高GA(C17：1)和GA(C15：1)血药浓度水平。此外,CsA还可以通过抑制脑中P-gp,增加GA(C17：1)和GA(C15：1)在脑中的分布。
Ginkgo biloba was widely used in the world as a drug for the prevention and treatment of cerebrovascular disease. Ginkgolic acid is a mixture of structurally related n-alkyl phenolic acid compounds and widely exists in leaves, nuts and external seed coat of Ginkgo biloba L. The alkyl side chain in molecular structures varies from13to19carbons in length with0-3double bonds. GA (C15:1) and GA (C17:1) are the two main ingredients accounted for nearly80%of the total ginkgolic acid. Ginkgolic acid is considered to be the toxic components of ginkgo with cytotoxicity, sensitization, mutagenic and carcinogenic, hepatotoxcity and nephrotoxicity. However, it was also reported that ginkgo acid has shown a wide range of pharmacological activities, including anti-bacterial, anti-inflammatory, anti-allergic, insecticidal, inhibition of the growth of a variety of tumor cells in vitro and in vivo as well as HIV protease activity and HIV infection in vitro. Most of the research focused on the pharmacological and toxicological aspects of ginkgolic acid, the reports about drug metabolism and pharmacokinetics of GAs are still rare. In this study, GA(C17:1) and GA(C15:1) were isolated and purified from the ginkgolic acid extract and their absorption, transport, metabolism, excretion and pharmacokinetics profiles were investigated by using several in vitro and in vivo models. The results of this study could provide theoretical and experimental basis for the further research of ginkgolic acid.
1. Metabolism of GA (C17:1) in rat liver microsomes
GA (C17:1) could be metabolized by CYPs (Phase I metabolism), and UGTs (Phase II metabolism). The special chemical inhibitor experiments indicated that CYP1A1/2and CYP3A were involved in GA (C17:1) oxidative metabolism; UGT1A7and UGT1A9were involved in GA (C17:1) glucuronidation metabolism. Classical CYPs' substrates were used to investigate the inhibition effect of GA (C17:1) on the CYPs, with the results that GA (C17:1) has inhibition effect on CYP2C6and no effect on CYP3A, CYP1A1/2, CYP2E1, CYP2D1. Three metabolites of GA (C17:1) in rat liver microsomes (RLMs) were analyzedas (two mono-hydroxylation metabolites and a glucuronidation metabolite) by LC-MS/MS.
2. Metabolism of GA (C17:1) in human liver microsomes, recombinant human CYPs and UGTs
The affinity of GA (C17:1) to human liver microsomes (HLMs) was less than that to RLMs. It was found that CYP3A4and CYP1A2were the two CYP enzyme isoforms that mediated the oxidative metabolism of GA (C17:1), UGT1A6, UGT1A9and UGT2B15were involved in GA (C17:1) glucuronidation metabolism. GA (C17:1) showed certain inhibition effect on CYP2C9. GA (C17:1) at10μmol/L showed no gene induction of CYP2B6and CYP3A4(<30%of rifampicin induction ability), concentration-dependent inductionof UGT1A1tested by dual-luciferase reporter assay.
3. The metabolism and toxicity of GA(C17:1) on HepG2, rat primary hepatocytes and L02cell
GA (C17:1) showed the different levels of toxicity on HepG2, rat primary hepatocytes and L02cell. Pretreatment with selective CYP inducers β-naphthoflavone and rifampin, could increase the cytotoxicity of ginkgolic acid (C17:1) in HepG2cells and rat primary hepatocytes. Co-incubation with selective CYP inhibitors a-naphthoflavone and ketoconazole could decrease the cytotoxicity of ginkgolic acid in primary rat hepatocytes. The results indicated that GA (C17:1) showed greater cytotoxicity on HepG2cells comparing with primary rat hepatocytes and L02cell, and CYP1A and3A catalyzed GA (C17:1) to more toxic metabolite.
4. Transport and uptake studies of GA (C17:1) and GA (C1S:1) in MDR1and BCRP transgenic cells
MDCK-MDR1and LLC-PK1-BCRP cells were adopted as the in vitro model to predict the intestinal absorption and blood-brain barrier (BBB) permeability. The results showed that GA (C17:1) and GA (C15:1) are the substrates of efflux transporters, P-gp and BCRP. GA (C17:1) and GA (C15:1) may have not very good oral bioavailability and BBB permeability. GA (C17:1) and GA (C15:1) had significant inhibition effects on the P-gp-mediated transport of R123across the MDCK-MDR1cell monolayer.
5. Plasma pharmacokinetics, tissue distribution, metabolism and excretion studies of ginkgolic acid (C17:1) in rats
A rapid and sensitive method for the determination of ginkgolic acid (C17:1) in rat biological samples was developed using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The pharmacokinetic investigation demonstrated that GA (C17:1) was rapidly absorbed with an absolute bioavailability being approximate19.5%. The tissue distribution indicated that liver and kidney were the major accumulation tissues for GA (C17:1) in rats. In addition, GA (C17:1) could hardly cross the blood-brain barrier. The excretion study suggested that feces was the main excretion pathway,while high proportion of GA (C17:1)(>35%) was excreted as the unchanged form. And two metabolites in feces were identified.
6. Pharmacokinetics of ginkgolic acid (C15:1) and ginkgolic acid (C17:1) in extract of external seed coat of ginkgo biloba L. in rat
A rapid and sensitive LC-MS/MS method for the simultaneous determination of ginkgolic aicd (C15:1) and ginkgolic aicd (C17:1) in rat plasma was developed and applied to investigate the pharmacokinetics of ginkgolic acid extract in rats. Compared with ginkgo acid monomers, the pharmacokinetic parameters of GA (C17:1) and GA (C15:1) has changed externally. Coadministrated intravenously P-gp and BCRP inhibitor CsA at20mg/kg can significantly improve GA (C17:1) and GA (C15:1) plasma concentration levels, CsA can also inhibit brain P-gp and BCRP, increased GA (C17:1) and GA (C15:1) distribution to the brain.
引文
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