XENOBIOTICA
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2018
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IF 1.857
Li Wang,Xiaodan Hong,Zhihong Yao,Yi Dai,Guoping Zhao,Zifei Qin,Baojian Wu,Frank J. Gonzalez,Xinsheng Yao
1. Icaritin is a natural flavonoid with anti-osteoporosis activity. This study aimed to characterize icaritin glucuronidation by pooled human liver microsomes (HLM) and pooled human intestine microsomes (HIM), and to determine the contribution of individual UDP-glucuronosyltrans-ferase (UGT) enzyme to icaritin glucuronidation.2. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid (UDPGA)-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Relative activity factors and activity correlation analysis were performed to identify main UGT isoforms.3. UGT1A3, 1A7, 1A8, 1A9 and 2B7 were mainly responsible for catalyzing the formation of two glucuronides (G1 and G2). Icaritin 3-O-glucuronidation (G1) was significantly correlated with Chenodeoxycholic acid (CDCA) glucuronidation (r = 0.787, p = 0.002), propofol glucuronidation (r = 0.661, p = 0.019) and Zidovudine (AZT) glucuronidation (r = 0.805, p = 0.002). Similarly, icaritin 7-O-glucuronidation (G2) was also correlated with CDCA glucuronidation (r = 0.640, p = 0.025), propofol glucuronidation (r = 0.592, p = 0.043) and AZT glucuronidation (r = 0.661, p = 0.019). In addition, UGT1A3, 1A9 and 2B7 contributed 37.5, 33.8 and 21.3% for G1 in pooled HLM, respectively. Also, UGT1A3, 1A9 and 2B7 contributed 34.3, 20.0 and 8.6% for G2 in pooled HLM, respectively.4. Icaritin was subjected to significant glucuronidation, wherein UGT1A3, 1A7, 1A8, 1A9 and 2B7 were main contributing enzymes.
研究领域:
药理学
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生物化学
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药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
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2012
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IF 1.848
Cong Liu,Yun-Feng Cao,Zhong-Ze Fang,Yan-Yan Zhang,Cui-Min Hu,Xiao-Yu Sun,Ting Huang,Jia Zeng,Xu-Ran Fan,Mo Hong
Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructus schisandrae which has been widely used as a tonic in traditional Chinese medicine for many years. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb–drug interaction. The aim of the present study is to investigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGT isoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM of deoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligible inhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin A were demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC 50 value of 10.8 ± 0.4 μM and 12.5 ± 0.5 μM, respectively. Dixon and Lineweaver–Burk plots showed that inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, and inhibition kinetic parameter (K i ) was calculated to be 0.48 μM. Inhibition of UGT1A3 by schisantherin A gave the best fit for types of noncompetitive inhibition, and the results showed K i to be 11.3 μM. All these experimental data suggested that herb–drug interaction might occur when deoxyschizandrin or schisantherin A containing herbs were co-administered with drugs which mainly undergo UGT1A3-mediated metabolism. However, given that many in vivo factors could influence the in vitro – in vivo extrapolation (IVIVE), these in vitro inhibitory parameters should be considered with caution.
研究领域:
中药学
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生物化学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2017
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IF 3.255
Yuan Wang,Qing Li,Yue Dai,Ronghua Pan,Yufeng Xia
A specific and sensitive LC–MS/MS method was established for the simultaneous determination of bergenin, protocatechuic acid and gallic acid, the main active constituents of Saxifraga stolonifera (L.) Meerb. herb, in rat plasma. After fully validated, the method was applied to the comparative pharmacokinetic studies of the three compounds orally administered alone and in combination in the S. stolonifera extract, respectively. The results showed that the pharmacokinetic parameters, including C max , T max , AUC, CL z /F, MRT 0-∞ , were significantly different for both bergenin and protocatechuic acid in the extract as compared to the corresponding compounds administered alone. However, the pharmacokinetic behavior of gallic acid in the extract did not differ from that administered alone. Further studies found that quercetin, coexisting in the herb extract, significantly decreased the glucuronidation of bergenin through inhibiting the activities of UGT1A1 and UGT1A3, and reduced the metabolism of protocatechuic acid by inhibiting the activity of catechol-O-methyltransferase. Quercetin and other flavonoids occurring in the S. stolonifera extract might increase the absorption and improve the bioavailability of bergenin and protocatechuic acid by slowing down the liver metabolism. The findings provide a good guidance for the development and clinical application of S. stolonifera .
研究领域:
药理学
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分析化学
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传统医学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2021
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IF 3.534
Zifei Qin,Peile Wang,Shuyi Duan,Xiaoying Wan,Han Xing,Jing Yang,Xiaojian Zhang,Zhihong Yao,Xinsheng Yao
Isobavachalcone, a naturally occurring chalcone in Psoralea corylifolia , posses many biological properties including anticancer, antiplatelet, and antifungal. However, its glucuronidation, glucuronides excretion, and drug-drug interaction (DDI) involving in human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) enzymes, and efflux transporters (BCRP and MRPs) remains unclear so far. After incubation, three glucuronides were produced by HLM and HIM with total intrinsic clearance ( CL int ) of 236.71 and 323.40 μL/min/mg, respectively. Reaction phenotyping proved UGT1A1, 1A3, 1A7, 1A8, and 1A9 played important roles in glucuronidation with total CL int values of 62.69–143.00 μL/min/mg. Activity correlation analysis indicated UGT1A1 and UGT1A3 participated more in the glucuronidation. In addition, the glucuronidation showed marked species differences, and rabbits and dogs were probably appropriate model animals to investigate the in vivo glucuronidation. Furthermore, BCRP , MRP1, and MRP4 transporters were identified as the most important contributors to glucuronides excretion in HeLa1A1 cells based on gene silencing method. Moreover, isobavachalcone demonstrated broad-spectrum inhibitory effects against CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 , UGT1A1, UGT1A9, UGT2B7 with IC 50 values of 1.08–9.78 μM. Except CYP2B6 and CYP2D6, the calculated [I]/ K i values for other enzymes were all greater than 0.1, indicating the inhibition of systemic metabolism or elimination for these enzyme substrates seems likely. Taken together, we summarized metabolic fates of isobavachalcone including glucuronidation and efflux transport as well as inhibitory effects involving in human CYP and UGT enzymes.
研究领域:
药理学
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生物化学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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