TOXICOLOGY LETTERS
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2021
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IF 4.374
Zhe Wang,Xiaoyu Wang,Zhen Wang,Yaqin Jia,Yuyi Feng,Lili Jiang,Yangliu Xia,Jun Cao,Yong Liu
Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a K i,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a K i,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [ I ] gut / K i,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.
研究领域:
药理学
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临床医学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
·
2024
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IF 1.9
Li Wenjing,Xue Yufan,Zhang Feng,Xiao Ling,Huang Zhu,Li Wenjuan,Zhu Liangliang,Ge Guangbo
Background and Objective Ciclopirox is a widely used antifungal drug, redisposition of which has drawn increasing attentions due to multiple promising activities. The drug undergoes extensive glucuronidation, which acts as a major obstacle in the ongoing novel application and still remains poorly understood. The current study aims to phenotype ciclopirox glucuronidation pathway and as well to decipher the related species differences. Methods Ciclopirox glucuronidation was investigated in liver microsomes from humans (HLM) and various experimental animals. Assays with recombinant uridine diphosphate glucuronosyltransferases (UGTs), enzyme kinetic analyses and selective inhibitors were used to determine the role of individual UGTs in ciclopirox glucuronidation. Results HLM is highly active in ciclopirox glucuronidation with Michaelis–Menten constant ( K m ), maximum velocity ( V max ), and intrinsic clearance (CL int ) values of 139 μM, 7.89 nmol/min/mg, and 56 μL/min/mg, respectively. UGT1A9 displays by far the highest activity, whereas several other isoforms (UGT1A6, UGT1A7, and UGT1A8) catalyze formation of traced glucuronides. Further kinetic analysis demonstrates that UGT1A9 has a closed K m value (167 μM) to HLM. UGT1A9 selective inhibitor (magnolol) can potently inhibit ciclopirox glucuronidation in HLM with the IC 50 value of 0.12 μM. The reaction displays remarkable differences across liver microsomes from mice, rats, cynomolgus monkey, minipig, and beagle dog, with the CL int values in the range of 26–369 μL/min/mg. In addition, ciclopirox glucuronidation activities of experimental animals’ liver microsomes were less sensitive to magnolol than that of HLM. Conclusions Ciclopirox glucuronidation displays remarkable species differences with UGT1A9 as a dominant contributor in humans. It is suggested that the pharmacological or toxicological effects of ciclopirox may be UGT1A9 and species dependent.
研究领域:
药理学
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生物化学
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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
Danyi Lu,Qian Xie,Baojian Wu
N -glucuronidation is an important pathway for metabolism and disposition of tertiary amines in humans. This reaction is mainly catalyzed by the enzymes UGT1A4 and UGT2B10. However, the metabolic patterns of UGT1A4- and UGT2B10-mediated N -glucuronidation are not fully clear. In this study, we first optimized in vitro reaction conditions for N -glucuronidation by using specific substrates (i.e., trifluoperazine for UGT1A4, cotinine and amitriptyline for UGT2B10). Furthermore, we found that hepatic N -glucuronidation showed significant species differences. In addition, UGT1A4 and UGT2B10 were primarily responsible for N -glucuronidation of many tertiary amines, including asenapine, loxapine, clozapine, chlorpromazine, dothiepin, doxepin, mirtazapine, mianserin, chlorcyclizine, cyclizine, promethazine, cyclobenzaprine, imatinib, retrorsine, strychnine and brucine. In conclusion, this study provides an in vitro assay system for evaluating N -glucuronidation of amines. Also, UGT1A4- and UGT2B10-mediated N -glucuronidation might play significant roles in metabolism and detoxification of tertiary amines in humans.
研究领域:
药理学
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生物化学
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药物代谢
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PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2018
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IF 2.831
Zifei Qin,Shishi Li,Zhihong Yao,Xiaodan Hong,Jinjin Xu,Pei Lin,Guoping Zhao,Frank J. Gonzalez,Xinsheng Yao
Corylin, an phenolic compound from Psoralea corylifolia , has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CL int (intrinsic clearance) values of 24.29 and 42.85 μL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CL int values of 26.63, 33.09 and 132.41 μL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin- N -deacetylation ( r = 0.885, p = 0.0001) and tolbutamide-4-oxidation ( r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 μL/min/mg) and in HIM (108.74 μL/min/mg). UGT1A1 contributed the most for M7 with the CL int value of 122.32 μL/min/mg. Meanwhile, M7 was significantly correlated with β-estradiol-3- O -glucuronidation ( r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo .
研究领域:
药理学
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生物化学
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PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2021
·Vol. 18
·期 10
·e2100388
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IF 2.408
Sisi Liu,Pei Deng,Yihong Long,Shushu Yang,Junshuo Zhu,Kunsheng Li,Changjiangsheng Lai,Weiran Yang,Jinlong Chen
Former study suggests alkaloids from herbs of Aconitum genus plants possess excellent bioactivities, which exert great value for related deeper chemical constituent investigation. Herein, chemical isolation was performed and four alkaloids were isolated from Fuzi , of which two were new ones, and the other two were reported NMR data for the first time. Their chemical structures were identified by NMR data, high resolution MS, UV and IR analysis. Additionally, the MS fragmentation patterns were explored, formerly, that of hetisane alkaloid was rarely reported, and fragmentation mechanism of the diagnostic ion was proposed. Based on these fragment pathway, metabolites and metabolic pathways of four compounds were investigated in rat liver microsomes using UPLC−Q/TOF−MS, and dehydrogenation product was firstly found from metabolites of hetisane alkaloid. Graphical
研究领域:
药理学
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天然产物化学
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DOI
高影响因子
Expert Opinion on Drug Metabolism & Toxicology
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2015
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IF 2.831
Danyi Lu,Dong Dong,Zhong Liu,Yifei Wang,Baojian Wu
Objective: The aim of this article is to elucidate the metabolic pathways of BJ-B11, a heat shock protein 90 inhibitor, in human liver microsomes (HLM) and determine the main enzymes responsible for formation of each metabolite.Methods: Metabolites of BJ-B11 were identified using the ultra performance liquid chromatography- quadrupole time-of-flight/mass spectrometry (UPLC-QTOF/MS) method. Esterase contributing to the hydrolysis of BJ-B11 was identified by chemical inhibition and activity correlation assays. Reaction phenotyping and kinetic studies using expressed cytochrome P450 (CYP) enzymes were performed to determine the contributions of CYP isozymes to BJ-B11 metabolism.Results: BJ-B11 was rapidly hydrolyzed to generate a deacetylated product M1-1. M1-1 was subsequently metabolized to form eight metabolites. Hydrolysis of BJ-B11 was markedly inhibited by vinblastine (a dual inhibitor of arylacetamide deacetylase and carboxylesterase 2). By contrast, digitonin and telmisartan (the specific inhibitors for carboxylesterase 1 and carboxylesterase 2, respectively) did not inhibit BJ-B11 hydrolysis at all. Further, BJ-B11 hydrolysis was significantly correlated with hydrolysis of phenacetin (an activity marker of arylacetamide deacetylase). Moreover, reaction phenotyping revealed that metabolism of M1-1 in HLM was attributable to several CYP enzymes, including CYP1A1, 1B1, 3A4 and 3A5.Conclusion: BJ-B11 was subjected to efficient metabolism in the liver, generating nine metabolites. BJ-B11 metabolism was contributed mainly by arylacetamide deacetylase and multiple CYP enzymes.
研究领域:
药理学
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生物化学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2017
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IF 3.858
Shuowen Tang,Ang Chen,Xiaojing Zhou,Li Zeng,Mingyao Liu,Xin Wang
Shikonin is a naphthoquinone pigment extracted from roots of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), and possesses various pharmaceutical activities, such as anti-inflammation and anti-cancer effects. In addition, shikonin as a natural red colorant for food garnishment and cosmetics ingredient is widely used in the world. However, the inhibition risk of shikonin on cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the potential inhibition of shikonin against CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver microsomes through cocktail approach in vitro. The results demonstrated that shikonin exhibited no time-dependent inhibition of CYP activities. In human liver microsomes, shikonin was not only a mixed inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4, but also a competitive inhibitor of CYP2E1, with K i values no more than 7.72 μM. In rat liver microsomes, shikonin also exhibited the mixed inhibition on CYP1A2, CYP2B1, CYP2C11, CYP2D1, and the competitive inhibition on CYP2E1. Interestingly, shikonin presented an atypical kinetic inhibition of CYP3A2-mediated midazolam 1-hydroxylation in rats. In conclusion, the relatively low K i values of shikonin would have a high risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions based on the potent inhibition of CYP enzymes.
研究领域:
药理学
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毒理学
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生物化学
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PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Wang Jinhui,Chen Feifei,Jiang Hui,Xu Jia,Meng Deru,Geng Peiwu,Dai Dapeng,Hu Jingbo,Zhou Yunfang,Zhou Quan,Wang Shuanghu
Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.
研究领域:
药理学
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临床医学
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生物化学
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DOI
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2025
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IF 3.1
Ming Li,Hua Sun,Jin-Ling Song,Xing Sun,Wei Li
I3,II8-biapigenin is a biflavonoid compound with diverse pharmacological effects. The present study aimed to investigate the glucuronidation of I3,II8-biapigenin in the human liver microsomes (HLMs) and recombinant human UDP-glucuronosyltransferases (UGTs). Three glucuronidation metabolites of I3,II8-biapigenin were detected in HLMs. Both recombinant human UGTs and chemical inhibitors studies demonstrated that UGT1A1, UGT1A3, UGT1A9 and UGT1A10 were involved in the glucuronidation of I3,II8-biapigenin. The present investigation provided information for the drug-drug interaction potentials of I3,II8-biapigenin when co-administrated with UGTs inhibitors or inducers.
研究领域:
药理学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Yuchen Wang,Qianyi Huang,Siqi Zhang,Shan Liu,Hengxiang Li,Xiaodong Wang,Yan Wang,Rui Hou,Xiangrong Xu
The ubiquitous occurrence of organic UV stabilizers (OUVs) poses a potential threat to marine fish, but the metabolism of OUVs in the body remains a missing piece of the puzzle in their ecotoxicology. This study investigated the in vitro metabolism of six OUVs in the liver microsomes of an economically valuable marine fish ( Lateolabrax japonicus ). The depletion of the six OUVs follows first-order kinetics in the microsomes, with in vitro depletion rate constants ( k depl ) ranging from 0.23 to 0.40/h. The intrinsic clearance ( CL int ) of 1H-benzotriazole (BT) was estimated to be 0.0026 μ L/(min·mg·protein). The enzyme inhibition experiments and molecular docking results highlight the importance of cytochrome P450 enzyme (CYP) 3A4 in OUVs metabolism. Among the 4 metabolizable compounds, some metabolites from hydroxylation, methylation, acetylation and conjugation were tentatively identified. In addition, the in vitro transformation rates can more accurately predict the whole-body bioconcentration potential via an in vitro to in vivo extrapolation (IVIVE) model.
研究领域:
环境科学
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毒理学
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鱼类生物学
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DOI
PubMed
高影响因子
RSC Advances
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2018
·Vol. 8
·期 72
·41368-41375
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IF 2.936
Liangliang He,Jinjin Xu,Qi Wang,Yezi Zhang,Zifei Qin,Yang Yu,Zhengming Qian,Zhihong Yao,Xinsheng Yao
Shogaols, mainly [6]-shogaol (6S), [8]-shogaol (8S) and [10]-shogaol (10S), the predominant and characteristic pungent phytochemicals in ginger, are responsible for most of its beneficial effects. However, poor oral bioavailability owing to extensive glucuronidation limits their application. The present study aimed to characterize the glucuronidation pathways of 6S, 8S and 10S by using pooled human liver microsomes (HLM), human intestine microsomes (HIM) and recombinant human UDP-glucosyltransferases (UGTs). The rates of glucuronidation were determined by incubating shogaols with uridine diphosphate glucuronic acid-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Reaction phenotyping assays, activity correlation analyses and relative activity factors were performed to identify the main UGT isoforms. As a result, one mono-4′-O-glucuronide was detected after incubating each shogaol with HLM and HIM. Enzymes kinetic analysis demonstrated that glucuronidation of shogaols consistently displayed the substrate inhibition profile, and the liver showed higher metabolic activity for shogaols (CLint = 1.37–2.87 mL min−1 mg−1) than the intestine (CLint = 0.67–0.85 mL min−1 mg−1). Besides, reaction phenotyping assays revealed that UGT2B7 displayed the highest catalytic ability (CLint = 0.47–1.17 mL min−1 mg−1) among all tested UGTs. In addition, glucuronidation of shogaols was strongly correlated with AZT glucuronidation (r = 0.886, 0.803 and 0.871 for glucuronidation of 6S, 8S and 10S, respectively; p < 0.01) in a bank of individual HLMs (n = 9). Furthermore, UGT2B7 contributed to 40.8%, 34.2% and 36.0% for the glucuronidation of 6S, 8S and 10S in HLM, respectively. Taken altogether, shogaols were efficiently metabolized through the glucuronidation pathway, and UGT2B7 was the main contributor to their glucuronidation.
研究领域:
药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
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2013
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IF 2.231
Ming Cong,Cui-Min Hu,Yun-Feng Cao,Zhong-Ze Fang,Shu-Hong Tang,Jia-Rui Wang,Jun-Sheng Luo
Danshen is one of the most famous herbs in the world, and more and more danshen–prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen–drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation. In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver–Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I. The second plot using the slopes from the Lineweaver–Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (K i ) to be 0.4 and 1.7 μM, respectively. Using the reported maximum plasma concentration (C max ), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively. All these results indicated the possible danshen–propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol.
研究领域:
药理学
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中药学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）