MOLECULES
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2012
·Vol. 17
·期 9
·10994-11009
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IF 2.386
Yunxia Zhang,Yunlan Li,Qingshan Li
The specific aims of this study were to evaluate the inhibition effect on CYP3A of di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT), a tin-based complex with high antitumor activity, and the probable mechanism(s) of this action. Adult male SD rats were treated separately with natural saline (NS), lipopolysaccharide (LPS, 5 mg/kg), DBDCT (1.25, 2.5 and 5.0 mg/kg) intraperitoneally for 2 days after induction of CYP3A with dexamethasone (DEX, 100 mg/kg) for 4 days. Western blot analysis and fluorescent quantitation PCR (FQ-PCR) were conducted to determine the changes in expression of CYP3A, PXR, CAR and RXR. The biological accumulation of DBDCT and total Sn were determined by high-performance liquid chromatography (HPLC) and atomic fluorescence spectrometry (AFS). CYP450 content and CYP3A activities were significantly inhibited (p< 0.05) in DBDCT-treated rats compared with the control group, as was the expression of CYP3A (p< 0.05) at both protein and mRNA levels. In DBDCT-treated groups, the expression of PXR protein and mRNA increased, while the expression of CAR decreased. The biological accumulation of DBDCT and Sn in rat livers treated with DBDCT was high. The accumulation of DBDCT and Sn due to the inhibition of CYP3A may be involved in the mechanism of toxicity of DBDCT in rat liver.Keywords:cytochrome P450 3A (CYP3A);di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV) (DBDCT);inhibition;rat
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
·
IF 5.811
Wei Jingyao,Liu Ruijuan,Zhang Jiali,Liu Shuaibing,Yan Dan,Wen Xueqian,Tian Xin
Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.
研究领域:
药理学
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肿瘤学
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药学
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临床研究
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Hongwei Yao,Jingkai Gu,Yuqin Shan,Yani Wang,Xue Chen,Dong Sun,Yingjie Guo
Patients with diabetic mellitus tend to have a poor response to clopidogrel (Clop) due to reduced generation of active metabolite (Clop-AM). However, the underlying mechanism is not elucidated. A type 2 diabetic mellitus (T2DM) rat model was established by combining high-fat diet feeding and low-dose streptozotocin (STZ) injection. The reduced Clop-AM exposure was observed in T2DM rats after oral administration of Clop. However, in vitro liver microsomes incubated with Clop exhibited increased Clop-AM levels in T2DM rats due to a significant decrease in carboxylesterase (CES)1 expression and activity and a significant increase in the expression or activity of CYP1A2 and CYP3A . Interestingly, different from oral administration, the significantly increased C max of Clop-AM was observed in T2DM rats after intravenous injection, with no difference in AUC 0-t and t 1/2 values between the two strains. Meanwhile, in situ single -pass intestinal perfusion study showed lower absorption rate constant ( K a) and effective apparent permeability values ( P eff ) of Clop in T2DM rats than in control rats. It is explained by the increased expression or function of P-glycoprotein (P-gp) and pregnane X receptor (PXR) in duodenum and jejunum of T2DM rats. Moreover, the decreased Clop-AM level in T2DM rats was eliminated by the pretreatment of cyclosporin A , a P-gp inhibitor. It suggests that intestinal absorption, not hepatic metabolism is responsible for the reduced Clop-AM exposure in T2DM rats. P-gp might be the key factor causing the reduction of Clop absorption, consequently making less Clop available for Clop-AM formation.
研究领域:
药理学
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糖尿病研究
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药学
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代谢
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2019
·Vol. 72
·期 3
·448-460
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IF 2.39
Zhang Jiaxin,Xie Qiushi,Kong Weimin,Wang Zhongjian,Wang Shuting,Zhao Kaijing,Chen Yang,Liu Xiaodong,Liu Li
ObjectivesTo investigate effects of short-chain fatty acids (SCFAs) on expressions and functions of intestinal cytochrome P4503A (Cyp3a) and P-glycoprotein (P-gp). To develop a semi-physiologically based pharmacokinetic (semi-PBPK) model for assessing their contributions.MethodsVerapamil pharmacokinetics was investigated following oral administration to rats receiving water containing 150 mm SCFAs for 3 weeks. Cyp3a activities in intestinal and liver mircosomes were assessed by norverapamil formation. In-situ single-pass perfusion was used to evaluate intestinal transport of verapamil and P-gp function. Functions and expressions of Cyp3a and P-gp were measured in mouse primary enterocytes following 48-h exposure to SCFAs. Contributions of intestinal P-gp and Cyp3a to verapamil pharmacokinetics were assessed using a semi-PBPK model.Key findingsShort-chain fatty acids significantly increased oral plasma exposures of verapamil and norverapamil. SCFAs upregulated Cyp3a activity and expression, but downregulated P-gp function and expression in rat intestine, which were repeated in mouse primary enterocytes. PBPK simulation demonstrated contribution of intestinal Cyp3a to oral plasma verapamil exposure was minor, and the increased oral plasma verapamil exposure was mainly attributed to downregulation of intestinal P-gp.ConclusionsShort-chain fatty acids oppositely regulated functions and expressions of intestinal Cyp3a and P-gp. The downregulation of P-gp mainly contributed to the increased oral plasma verapamil exposure by SCFAs.
研究领域:
药理学
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药代动力学
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胃肠科学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
·
IF 5.195
Kun Ren,Ruijie Wang,Shinuo Fang,Shumeng Ren,Huiming Hua,Dongmei Wang,Yingni Pan,Xiaoqiu Liu
Ethnopharmacological relevance As a traditional Chinese medicine , Euodiae Fructus (EF) has been used to treat stomachache, belching, and emesis for more than a thousand years. Ancient records and modern research have shown that EF has mild toxicity, which needs to be processed with licorice juice to reduce its toxicity. Research suggested that the toxicity of EF can be caused by in vivo metabolism , but whether its metabolites are related to hepatotoxicity and whether licorice can affect the metabolism of EF have not been reported, which needed an effective strategy to clarify the correlation between metabolites and toxicity and the attenuation mechanism of licorice processing. Aim of the study The poisonous substances and metabolic pathways were clarified by comparing the mechanism in vivo process of the main alkaloids of EF in normal rats and rats treated with dexamethasone (DXMS), ketoconazole (KTC), and EF processed with licorice (EFP). Materials and methods Rats were given EF and EFP by oral administration, respectively. The EF + DXMS and EF + KTC groups were pretreated with DXMS and KTC, respectively, by i. p. for seven days, and their toxicity differences were compared. The comprehensive strategy based on UPLC-Q-Exactive-MS and Orthogonal Partial Least Squares Discriminant Analysis was developed to compare the types and contents of metabolites and clarify the metabolic pathways of alkaloids among EF, EFP, EF + KTC, and EF + DXMS groups. Results EF + DXMS group significantly increased the hepatotoxicity, whereas the EF + KTC and EFP groups reduced the hepatotoxicity compared with the EF group. One hundred and thirty-five metabolites were detected, and the metabolic pathways of the main alkaloid components related to toxicity were inferred in the plasma, urine, feces, and bile of rats. KTC and licorice similarly inhibited the production of toxic metabolites, changed metabolism in vivo, and produced many new II and a few phases I metabolites, while the contents of toxic metabolites increased in the DXMS group. Conclusion Licorice and KTC could inhibit the production of metabolites of EF related to toxicity, increase the production of other metabolites and promote the excretion of alkaloids, which may be why licorice and KTC can minimize EF toxicity.
研究领域:
药理学
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毒理学
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中药学
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代谢组学
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分析化学
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PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY
·
2021
·Vol. 41
·期 1
·230-239
·
IF 3.742
Siqi Wu,Huizhen Li,Jing You
Fipronil has been frequently detected in waterways worldwide at concentrations that threaten aquatic organisms, yet the metabolic behavior of fipronil enantiomers in aquatic organisms is largely unknown, which is of significance in enantioselective toxicity evaluation. We quantitatively identified the specific cytochrome P450 (CYP) isozymes involved in metabolizing fipronil enantiomers in tilapia by combining in vitro metabolic kinetic assays and molecular docking. Inhibition studies suggested that CYP1A enzyme was the main isoform catalyzing metabolism of fipronil and that CYP3A contributed in a limited way to the metabolism in fish liver S9. Both the dissipation rate constant and the maximum metabolic velocity of R -(−)-fipronil were greater than those of S -(+)-fipronil in tilapia liver S9, suggesting that tilapia selectively metabolized R -(−)-fipronil. The CYP1A1 isozyme exhibited the highest binding capacity to R -(−)-fipronil and S -(+)-fipronil (binding energy ‒9.39 and ‒9.17 kcal/mol, respectively), followed by CYP1A2 (‒7.30 and ‒6.94 kcal/mol, respectively) and CYP3A4 (‒7.16 and ‒6.91 kcal/mol, respectively). The results of in vitro metabolic assays and molecular docking were consistent, that is, CYP1A, specifically CYP1A1, exhibited a higher metabolic capacity to fipronil than CYP3A, and fish liver S9 selectively metabolized R -(−)-fipronil. The present study provides insight into the enantioselective metabolic behavior and toxicological implications of the in vitro metabolic kinetics of fipronil in fish. Environ Toxicol Chem 2022;41:230–239. © 2021 SETAC
研究领域:
环境毒理学
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水生毒理学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）