The liver is an important organ for drugs disposition,and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing.However,there are many limitations in drug dosage adjustment based on liv...The liver is an important organ for drugs disposition,and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing.However,there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing.In this study,we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate(GCDCA-S)and 4β-hydroxycholesterol(4β-HC)plasma levels to evaluate organic anion-transporting polypeptide(Oatps)-mediated hepatic uptake and Cyp3 a-meidated metabolism of atorvastatin(ATV)in rats.The concentration of ATV and its metabolites,2-OH ATV and 4-OH ATV,was markedly increased after a single injection of rifampicin(RIF),an inhibitor of Oatps.Concurrently,plasma GCDCA-S levels were also elevated.After a single injection of the Cyp3 a inhibitor ketoconazole(KTZ),plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased,consistent with the metabolism of ATV by Cyp3 a.However,plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3 a metabolite of cholesterol.After repeated oral administration of RIF,plasma concentrations of ATV,2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased.KTZ did not affect plasma concentrations of ATV,2-OH ATV and 4-OH ATV,but significantly decreased the metabolic ratio of total and 4-OH ATV.However,the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ.The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF.Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury,respectively.These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV.However,Cyp3 a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.展开更多
Objective: To study the quinoline alkaloids from the ethanol extract of Scolopendra subspinipes mutilans(SSM).Methods: The chemical constituents were isolated and purified by macroporous resin column, medium pressure ...Objective: To study the quinoline alkaloids from the ethanol extract of Scolopendra subspinipes mutilans(SSM).Methods: The chemical constituents were isolated and purified by macroporous resin column, medium pressure preparation chromatography, and semi-preparative HPLC. Their structures were elucidated by IR,MS, and NMR experiments.Results: Three quinolone alkaloids were obtained and identified as 3-hydroxy-4-methoxyquinolin-8-yl hydrogen sulfate(1), jineol-8-sulfate(2), and jineol(3), respectively.Conclusion: Compound 1 is a new compound from SSM.展开更多
基金supported by National Natural Science Foundation of China(Grant No.81803611)。
文摘The liver is an important organ for drugs disposition,and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing.However,there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing.In this study,we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate(GCDCA-S)and 4β-hydroxycholesterol(4β-HC)plasma levels to evaluate organic anion-transporting polypeptide(Oatps)-mediated hepatic uptake and Cyp3 a-meidated metabolism of atorvastatin(ATV)in rats.The concentration of ATV and its metabolites,2-OH ATV and 4-OH ATV,was markedly increased after a single injection of rifampicin(RIF),an inhibitor of Oatps.Concurrently,plasma GCDCA-S levels were also elevated.After a single injection of the Cyp3 a inhibitor ketoconazole(KTZ),plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased,consistent with the metabolism of ATV by Cyp3 a.However,plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3 a metabolite of cholesterol.After repeated oral administration of RIF,plasma concentrations of ATV,2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased.KTZ did not affect plasma concentrations of ATV,2-OH ATV and 4-OH ATV,but significantly decreased the metabolic ratio of total and 4-OH ATV.However,the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ.The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF.Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury,respectively.These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV.However,Cyp3 a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.
基金supported by the Special Project (No. 1811) for the Scientific & Technological Innovation and Development of Lanshan District, Linyi
文摘Objective: To study the quinoline alkaloids from the ethanol extract of Scolopendra subspinipes mutilans(SSM).Methods: The chemical constituents were isolated and purified by macroporous resin column, medium pressure preparation chromatography, and semi-preparative HPLC. Their structures were elucidated by IR,MS, and NMR experiments.Results: Three quinolone alkaloids were obtained and identified as 3-hydroxy-4-methoxyquinolin-8-yl hydrogen sulfate(1), jineol-8-sulfate(2), and jineol(3), respectively.Conclusion: Compound 1 is a new compound from SSM.
