This study explored the effects of cucurbitacin E(Cu E), a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression in...This study explored the effects of cucurbitacin E(Cu E), a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression in rats. Liquid chromatography-(tandem) mass spectrometry(LC-MS/MS) assay was used to detect tolbutamide as well as 4-hydroxytolbutamide, and then successfully applied to the pharmacokinetic study of tolbutamide in rats. The effect of Cu E on CYP2C11 expression was determined by western blot. Cu E(1.25–100 μmol L-1) competitively inhibited tolbutamide 4-hydroxylation(CYP2C11) activity only in concentration-dependent manner with a Ki value of 55.5 μmol L-1 in vitro. In whole animal studies, no significant difference in metabolism/pharmacokinetic of tolbutamide was found for the single pretreatment groups. In contrast, multiple pretreatments of Cu E(200 μg kg-1 d-1, 3 d, i.p.) significantly decreased tolbutamide clearance(CL) by 25% and prolonged plasma half-time(T1/2) by 37%. Moreover, Cu E treatment(50–200 μg kg-1 d-1, i.p.) for 3 d did not affect CYP2C11 expression. These findings demonstrated that CuE competitively inhibited the metabolism of CYP2C11 substrates but had no effect on rat CYP2C11 expression. This study may provide a useful reference for the reasonable and safe use of herbal or natural products containing Cu E to avoid unnecessary drug-drug interactions.展开更多
基金supported by the National Natural Science Foundation of China (81301908)the Science and Technology Commission of Shanghai Municipality (13ZR1412600, 14DZ2270100)
文摘This study explored the effects of cucurbitacin E(Cu E), a bioactive compound from Cucurbitaceae, on the metabolism/ pharmacokinetic of tolbutamide, a model CYP2C9/11 probe substrate, and hepatic CYP2C11 expression in rats. Liquid chromatography-(tandem) mass spectrometry(LC-MS/MS) assay was used to detect tolbutamide as well as 4-hydroxytolbutamide, and then successfully applied to the pharmacokinetic study of tolbutamide in rats. The effect of Cu E on CYP2C11 expression was determined by western blot. Cu E(1.25–100 μmol L-1) competitively inhibited tolbutamide 4-hydroxylation(CYP2C11) activity only in concentration-dependent manner with a Ki value of 55.5 μmol L-1 in vitro. In whole animal studies, no significant difference in metabolism/pharmacokinetic of tolbutamide was found for the single pretreatment groups. In contrast, multiple pretreatments of Cu E(200 μg kg-1 d-1, 3 d, i.p.) significantly decreased tolbutamide clearance(CL) by 25% and prolonged plasma half-time(T1/2) by 37%. Moreover, Cu E treatment(50–200 μg kg-1 d-1, i.p.) for 3 d did not affect CYP2C11 expression. These findings demonstrated that CuE competitively inhibited the metabolism of CYP2C11 substrates but had no effect on rat CYP2C11 expression. This study may provide a useful reference for the reasonable and safe use of herbal or natural products containing Cu E to avoid unnecessary drug-drug interactions.
基金supported by the National Natural Science Fund of China(Nos.81102336,81102849)the Special Project of Biological Medicine of Science and Technology Commission of Shanghai Municipality(No.10431900500)~~
