PHARMACEUTICAL RESEARCH
·
2003
·Vol. 20
·期 9
·1401-1408
·
IF 2.354
Wanchana Suchada,Yamashita Fumiyoshi,Hashida Mitsuru
Purpose . To develop a quantitative structure/activity relationship (QSAR) model for predicting drug-CYP 3A4 interactions.
Method . The inhibitory effect of 53 structurally diverse drugs on the metabolism of 7-benzyloxy-4-trifluoromethyl coumarin (BFC) by recombinant CYP 3A4 was evaluated using a rapid microtiter plate assay. For each drug, a total of 220 two-dimensional topological indices were calculated using Molconn-Z software. Using a genetic algorithm-based partial least squares (GA-PLS) method, the desired descriptors were automatically selected to maximize the predictability of the IC 50 values.
Results . The IC 50 values of the drugs tested ranged from 9 nM to 2 mM. Based on the GA-PLS method, five principal components derived from 20 Molconn-Z descriptors were found to be effective for QSAR modeling. Interestingly, these descriptors suggested that the molecular size would be an important factor in determining drug-CYP 3A4 interactions. In the leave-one-out prediction, the r
pred and the standard error of prediction ( s ) were 0.754 and 0.787, respectively. Even in an external validation, the predictions were in good agreement with experimental values ( r
pred = 0.744, s = 0.769, n = 9).
Conclusions . The proposed model, in which two-dimensional topological descriptors were used as molecular descriptors, was able to predict drug-CYP 3A4 interactions with reasonable accuracy.
研究领域:
药理学
·
计算生物学
·
药物化学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
·
2023
·
IF 4.9
Minjun Ye,Bingyi Li,Wanyu Shi,Huaize Liu,Yi Wang,Weiqing Chen,Jian Wang,Guixue Wang
Radiation therapy has been widely used in the clinical treatment of tumors. Due to the low radiation absorption of tumors, a high dose of ionizing radiation is often required during radiotherapy, which causes serious damage to normal tissues near tumors. Boron neutron capture therapy (BNCT) is more targeted than conventional radiotherapy. To improve the therapeutic effect of cancer, albumin was selected as the drug carrier to wrap the fluorescent tracer boron drug BS-CyP and prepare the nanoparticles. Then, we developed a novel tumor-targeting nano-boron drug by using hyaluronic acid to modify the nanoparticles. We found that BS-CyP albumin nanoparticles modified with hyaluronic acid effectively delayed drug release and enhanced the aggregation, in tumors, showing good safety with no obvious toxicity to cells and mice. This study confirmed the advantages of boron drugs modified with hyaluronic acid targeting tumors and may provide a reference for BNCT.
研究领域:
肿瘤学
·
纳米技术
·
药学
·
放射治疗
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
·
2023
·Vol. 48
·期 5
·595-614
·
IF 1.9
Han Yiran,Wen Tiantian,Wang Jia,Shi Jinmiao,Zhu Yongqiang
Background and Objectives Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research. Methods The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated. Results Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1–4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed. Conclusion Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate. Graphical Abstract
研究领域:
肿瘤学
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药物代谢
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2018
·
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
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Natural Product Communications
·
2019
·
IF 0.554
Keling Cheng,Xuan Zeng,Hao Wu,Weiwei Su,Weiyang Fan,Yang Bai,Hongliang Yao,Peibo Li
Naringin (NRG) is a common dietary flavonoid in citrus fruits and has been documented to possess multiple pharmacological activities, including anti-oxidant, anti-inflammatory, and neuroprotective effects. Naringin is frequently consumed in combination with common clinical drugs. To date, the effects of NRG on cytochrome P450 enzymes have not been fully investigated yet. In this study, the activities of hepatic CYP1A2, CYP2D2, CYP2C9, CYP2C19, and CYP2E1 in rats after the continuous oral administration of NRG (50 and 500 mg/kg) were evaluated using cocktail probe-drug method. The concentrations of 5 probe drugs (phenacetin, dextromethorphan, diclofenac sodium, omeprazole, and chlorzoxazone) in rat plasma were simultaneously determined with a validated HPLC-MS/MS (high performance liquid chromatography-tandem mass spectrometry) method and then used to calculate corresponding pharmacokinetic parameters. Compared with the control group, the AUC(0-t), AUC(0-∞), t 1/2, and C max of each probe drug in treatment groups showed no significant differences. Meanwhile, fluorescence quantitative polymerase chain reaction (FQ-PCR) analysis revealed that NRG did not significantly affect the mRNA expressions of genes CYP1a2, CYP2d2, CYP2c6, CYP2c11, and CYP2e1 in rat liver. Based on these results, it could be concluded that NRG showed no significant effects on the activities and mRNA expressions of tested CYP450 in rats.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY LETTERS
·
2025
·
IF 2.9
Leina Jia,Xiaoning Meng,Yu Ma,Jinyu Luo,Xiaoqi Luo,Huifang Yang,Jian Zhou
Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765+CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.
研究领域:
毒理学
·
内分泌学
·
细胞生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2022
·
IF 6.388
Yuanjin Zhang,Jing Gao,Yuan Xu,Jie Liu,Shengbo Huang,Guihong Li,Bingyi Yao,Zhenliang Sun,Xin Wang
Deoxyshikonin, a natural naphthoquinone compound extracted from Lithospermum erythrorhizon Sieb. et Z ucc (Boraginaceae), has a wide range of pharmacological activities, including anti-tumor, anti-bacterial and wound healing effects. However, the inhibitory effect of deoxyshikonin on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of deoxyshikonin on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach in vitro . The single-point inactivation experiment showed that deoxyshikonin presented no time-dependent inhibition on CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that in HLMs, deoxyshikonin was not only a competitive inhibitor of CYP1A2 and 2E1, but also a mixed inhibitor of CYP2B6, 2C9, 2D6 and 3A4, with K i of 2.21, 1.78, 1.68, 0.20, 4.08 and 0.44 μM, respectively. In RLMs, deoxyshikonin not only competitively inhibited CYP2B1 and 2E1, but also exhibited mixed inhibition on CYP1A2, 2C11, 2D1 and 3A2, with K i values of no more than 18.66 μM. In conclusion, due to the low K i values of deoxythiokonin on CYP enzymes in HLMs, this may lead to drug–drug interactions (DDI) and potential toxicity.
研究领域:
药理学
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酶学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2022
·Vol. 13
·期 4
·983-993
·
IF 5.671
Tong Le,Zhou ZeYang,Wang Gang,Wu Chao
Oral absorption of docetaxel was limited by drug efflux pump p-glycoprotein (P-gp) and cytochrome P450 enzyme (CYP 450). Therefore, co-loading agent that inhibits P-gp and CYP450 in self-nanoemulsifying drug delivery systems (SMEs) is considered a promising strategy for oral delivery of docetaxel. In this study, curcumin was selected as an inhibitor of P-gp and CYP450, and it was co-encapsuled in SMEs to improve the oral bioavailability of docetaxel. SMEs quickly dispersed in water within 20 s, and the droplet size was 32.23 ± 2.21 nm. The release rate of curcumin from DC-SMEs was higher than that of docetaxel in vitro. Compared with free docetaxel, SMEs significantly increased the permeability of docetaxel by 4.6 times. And competitive experiments showed that the increased permeability was the result of inhibition of p-gp. The half-life and oral bioavailabilty of DC-SMEs increased about 1.7 times and 1.6 times than docetaxel SMEs, which indicated that its good pharmacokinetic behavior was related to the restriction of hepatic first-pass metabolism. In conclusion, DC-SME was an ideal platform to facilitate oral delivery of docetaxel through inhibited P-gp and CYP 450. Graphical Abstract
研究领域:
药剂学
·
药理学
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Jing Liu,Zhengjie Wang,Shuo Yin,Zhonghao Wang,Meng Wu,Jianhua Qin,Junlong Liu,Chuanwen Wang
Dermanyssus gallinae is a significant haematophagous ectoparasite of laying hens. Despite the worldwide application of beta-cypermethrin for mite control, resistance to this compound has been developed by D. gallinae . P450s, as key detoxification enzymes involved in the metabolism of exogenous and endogenous chemical substances, have not been functionally characterized in D. gallinae . Here, the role of the P450s gene (Deg-CYP-3) of D. gallinae in acaricide resistance was studied. Firstly, P450s activities of the five beta-cypermethrin resistant strains (RR) against p-nitroanisole were significantly higher than that of the susceptible strain (RS), suggesting enhanced enzymatic activities might contribute to mite beta-cypermethrin resistance. Both mRNA expression level and DNA copy number of Deg-CYP-3 were significantly higher in RR than in RS, except for DK RR strain. Moreover, recombinant Deg-CYP-3 (rCYP-3) expressed in Escherichia coli displayed high enzymatic activity against p-nitroanisole, while Qulaton-100, acetone, isoacetone, avermectin, and ivermectin were found to inhibit this activity. Immunohistochemical analysis revealed the presence of Deg-CYP-3 protein in the digestive tract and Malpighian tubules. Finally, silencing of Deg-CYP-3 via RNAi resulted in decreased enzyme activity and increased susceptibility of PG RR strain to beta-cypermethrin, confirming that Deg-CYP-3 is crucial for beta-cypermethrin detoxification. RNAi also resulted in enhanced mortality, as well as reduced oviposition and fecundity in the PG RR strain. Collectively, these findings indicate that resistance of D. gallinae to beta-cypermethrin is associated with elevated P450s protein activity and increased Deg-CYP-3 expression levels. The results provide insights into the metabolic resistance mechanisms of D. gallinae and offer scientific guidance for the management and control of mite.
研究领域:
寄生虫学
·
农药毒理学
·
分子生物学
·
兽医昆虫学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY IN VITRO
·
2025
·
IF 2.7
Pinzheng Li,Hengbin Zhang,Yingchun Chen,Shuanghui Lu,Huidi Jiang,Su Zeng,Hui Zhou
Oxoglaucine (OXO), an aporphine alkaloid derived from Corydalis yanhusuo , exhibits a broad spectrum of pharmacological activities, including antiviral, antifungal, antiplatelet, and anti-hepatic fibrosis effects, with particularly promising anticancer potential. In this study, we systematically investigated the hepatotoxicity profile and underlying mechanisms of OXO using in vitro models. Dose–response assays revealed that while OXO induced significant cytotoxicity in hepatocytes, primary hepatocytes exhibited markedly reduced sensitivity compared to hepatocellular carcinoma cells at therapeutically relevant concentrations. Mechanistic studies in mouse primary hepatocytes and human primary hepatocytes attributed this selective cytotoxicity to differential cytochrome P450 (CYP) enzyme expression. This finding was functionally validated by the observation that co-treatment with the broad-spectrum CYP inhibitor aminobenzotriazole (ABT) enhanced OXO-induced toxicity in mouse primary hepatocytes and human primary hepatocytes. Regarding its mechanism of toxicity, OXO induced marked cytotoxicity in the HepG2 cell line by triggering mitochondrial-mediated apoptosis, as evidenced by a decreased Bcl-2/Bax ratio, cytochrome C release, Caspase-3 activation, and S-phase cell cycle arrest. Collectively, our findings in HepG2 cells and primary hepatocytes elucidate the role of CYP-mediated metabolism in the selective cytotoxicity of OXO. These findings not only provide crucial mechanistic insights but also support the further development of OXO as a promising candidate for preclinical and clinical evaluation in hepatocellular carcinoma.
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PubMed
高影响因子
PHARMAZIE
·
2012
·Vol. 67
·期 12
·1002-1006
·
IF 1.006
Dong Rui-Hua,Fang Zhong-Ze,Zhu Liang-Liang,Ge Guang-Bo,Cao Yun-Feng,Li Xiao-Bao,Hu Cui-Min,Yang Ling,Liu Ze-Yuan
Carvacrol and thymol are phenolic compounds with similar structures isolated from many aromatic plants, and have been demonstrated to exert multiple pharmacological effects. The metabolic and pharmacokinetic behaviour of thymol and carvacrol has received much attention. Carvacrol and
thymol have been demonstrated to undergo phase I metabolism such as hydroxylation reaction. However, drug-metabolizing enzymes involved in this process remain unclear. Given that cytochrome P450 s (CYPs) are involved in most phase I metabolism, the aim of the present study was to investigate
the role of CYPs in the metabolism of thymol and carvacrol. After incubation with human liver microsomes (HLMs) in the presence of NADPH, a new metabolite and two metabolites were detected for thymol and carvacrol, respectively. A combination of chemical inhibition studies and assays with
recombinant CYP isoforms demonstrated that CYP2A6 was the predominant drug-metabolizing enzyme involved in the metabolism of thymol and carvacrol. All these results remind the researchers that special attention should be paid on pharmacokinetic and clinical outcomes when thymol or carvacrol
was co-administrated with other compounds mainly undergoing CYP2A6-mediated metabolism.
研究领域:
药理学
·
生物化学
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产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2019
·
IF 3.361
Sen Yang,Ge Kuang,Rong Jiang,Shengwang Wu,Tao Zeng,Yuanyuan Wang,Fangzhi Xu,Lingyi Xiong,Xia Gong,Jingyuan Wan
Acetaminophen (APAP) is a widely used over-the-counter drug for antipyretic and analgesic , but an overdose will induce acute liver injury. APAP hepatotoxicity has been the most common cause of acute liver failure in western countries with high morbidity and mortality. Geniposide (GP), an iridoid glycoside extracted from the fruit of Gardenia jasminoides , has been reported to exert a profound anti-inflammatory activity on acute and chronic diseases. However, it is never demonstrated whether GP can protect hepatocytes from APAP hepatotoxicity. In this study, we investigated the protective effect and underlying mechanism of GP against AILI. The results showed that GP pretreatment reduced the levels of ALT and AST in a dose-dependent manner and alleviated hepatocyte necrosis and apoptosis in mice exposed at APAP. Moreover, it suppressed the expression of CYP 2E1 and attenuated the exhaustion of GSH and accumulation of MDA in the liver. Furthermore, GP remarkably inhibited inflammatory cells infiltration and mitigated the release of IL-1β and TNF-α, and inhibited Toll-like receptor 4 (TLR4) expression and nuclear factor kappa (NF-κB) activation. These data suggested that GP could effectively protect hepatocytes from APAP hepatotoxicity through the down-regulation of CYP 2E1 expression and the inhibition of TLR4/NF-κB signaling pathway .
研究领域:
药理学
·
毒理学
·
肝病学
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产品关联
DOI
PubMed
高影响因子
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