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Abstract：
BACKGROUND: Ginkgo biloba L. is a traditional Chinese medicine for hyper lipaemia. Ginkgo flavonols and terpene lactones are responsible for the lipid-lowering effect in non-alcoholic fatty liver disease (NAFLD). However, the pharmacokinetics of ginkgo flavonols and terpene lactones in NAFLD was not clarified.
OBJECTIVE: To investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats.
METHODS: Male rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of 3H-ES were tested in hOATP1B1-HEK293 cells.
RESULTS: The plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6-32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2-3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the Cmax and AUC0-t of pitavastatin by 1.8-3.2 and 1.3-3.0 folds, respectively. In hOATP1B1-HEK293 cells, kaempferol and isorhamnetin contributed to the inhibition of OATP1B1-mediated uptake of 3H-ES with IC50 values of 3.28 ± 1.08 μM and 46.12 ± 5.25 μM, respectively.
CONCLUSIONS: NAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.
OBJECTIVE: To investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats.
METHODS: Male rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of 3H-ES were tested in hOATP1B1-HEK293 cells.
RESULTS: The plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6-32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2-3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the Cmax and AUC0-t of pitavastatin by 1.8-3.2 and 1.3-3.0 folds, respectively. In hOATP1B1-HEK293 cells, kaempferol and isorhamnetin contributed to the inhibition of OATP1B1-mediated uptake of 3H-ES with IC50 values of 3.28 ± 1.08 μM and 46.12 ± 5.25 μM, respectively.
CONCLUSIONS: NAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.
摘要：
背景：银杏是治疗高血脂的传统中药。银杏黄酮醇和萜内酯在非酒精性脂肪性肝病（NAFLD）中具有降脂作用。然而,银杏黄酮醇和萜内酯在NAFLD中的药代动力学尚未明确.
目的：研究银杏叶提取物（EGB）和NAFLD对肝细胞有机阴离子转运多肽（Oatp）1b2的影响，并评估EGB活性成分在NAFLD大鼠体内的药代动力学。
方法：雄性大鼠饲喂高脂饮食诱导NAFLD模型。在用3.6、10.8和32.4mg/kgEGB治疗2或4周后，在NAFLD大鼠中研究了EGB活性成分的药代动力学特征。研究了NAFLD和EGB对匹伐他汀全身暴露的影响，Oatp1b2的探针底物。在hOATP1B1-HEK293细胞中测试了银杏黄酮醇和萜内酯对OATP1B1介导的3H-ES摄取的抑制作用。
结果：在口服3.6-32.4mg/kg的EGB后，NAFLD大鼠的银杏内酯和黄酮醇的血浆暴露呈剂量依赖性增加。银杏内酯A的半衰期,B,C,白果内酯（2-3小时）短于槲皮素，山奈酚,和异鼠李素（约20小时）。由于大鼠肝脏中Oatp1b2表达增加,NAFLD使血浆匹伐他汀暴露减少约50%。EGB的增加（从3.6到32.4mg/kg）使匹伐他汀的Cmax和AUC0-t增加了1.8-3.2和1.3-3.0倍，分别。在hOATP1B1-HEK293细胞中，山奈酚和异鼠李素有助于抑制OATP1B1介导的3H-ES摄取，IC50值为3.28±1.08μM和46.12±5.25μM，分别。
结论：NAFLD和EGB可以单独或联合改变肝脏摄取转运体Oatp1b2的活性。在这项研究中发现的药代动力学草药-疾病-药物相互作用将有助于告知EGB或Oatp1b2底物的临床施用。
目的：研究银杏叶提取物（EGB）和NAFLD对肝细胞有机阴离子转运多肽（Oatp）1b2的影响，并评估EGB活性成分在NAFLD大鼠体内的药代动力学。
方法：雄性大鼠饲喂高脂饮食诱导NAFLD模型。在用3.6、10.8和32.4mg/kgEGB治疗2或4周后，在NAFLD大鼠中研究了EGB活性成分的药代动力学特征。研究了NAFLD和EGB对匹伐他汀全身暴露的影响，Oatp1b2的探针底物。在hOATP1B1-HEK293细胞中测试了银杏黄酮醇和萜内酯对OATP1B1介导的3H-ES摄取的抑制作用。
结果：在口服3.6-32.4mg/kg的EGB后，NAFLD大鼠的银杏内酯和黄酮醇的血浆暴露呈剂量依赖性增加。银杏内酯A的半衰期,B,C,白果内酯（2-3小时）短于槲皮素，山奈酚,和异鼠李素（约20小时）。由于大鼠肝脏中Oatp1b2表达增加,NAFLD使血浆匹伐他汀暴露减少约50%。EGB的增加（从3.6到32.4mg/kg）使匹伐他汀的Cmax和AUC0-t增加了1.8-3.2和1.3-3.0倍，分别。在hOATP1B1-HEK293细胞中，山奈酚和异鼠李素有助于抑制OATP1B1介导的3H-ES摄取，IC50值为3.28±1.08μM和46.12±5.25μM，分别。
结论：NAFLD和EGB可以单独或联合改变肝脏摄取转运体Oatp1b2的活性。在这项研究中发现的药代动力学草药-疾病-药物相互作用将有助于告知EGB或Oatp1b2底物的临床施用。
