In vitro and in vivo evaluation of cucurbitacin E on rat hepatic CYP2C11 expression and activity using LC-MS/MS.
This study explored the effects of cucurbitacin E (CuE), 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 CuE on CYP2C11 expression was determined by western blot. CuE (1.25-100 μmol L-1) competitively inhibited tolbutamide 4-hydroxylation (CYP2C11) activity only in concentration-dependent manner with a Kivalue of 55.5 μmol L-1in 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 CuE (200 μg kg-1d-1, 3 d, i.p.) significantly decreased tolbutamide clearance (CL) by 25% and prolonged plasma half-time (T1/2) by 37%. Moreover, CuE treatment (50-200 μg kg-1d-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 CuE to avoid unnecessary drug-drug interactions.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Jian
J
Lu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
TongGui
T
Ding
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Xuan
X
Qin
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
MingYao
M
Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. usxinwang@hotmail.com.
Xin
X
Wang
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D000072467:Cytochrome P450 Family 2 / Q000378:metabolism*; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014315:Triterpenes / Q000494:pharmacology*
C516573:4'-hydroxytolbutamide; D014315:Triterpenes; D014044:Tolbutamide; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C102326:cucurbitacin E
CYP2C11; LC-MS/MS; cucurbitacin E; pharmacokinetic; tolbutamide