DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 12
·1651-1662
·
IF 3.9
Xue Zhang,Jianquan Pan,Xi Ye,Yunna Chen,Lei Wang,Xiangyun Meng,Weidong Chen,Fengling Wang
Reduced enzyme activity in hepatocellular carcinoma (HCC) and poor targeting limit the application of enzyme-activating prodrugs, which is also detrimental to the effective treatment of HCC. Here, we investigated whether accelerated blood clearance (ABC) phenomenon occurs in HCC models following repeated injections of PEGylated liposomes (PEG-L), thus inducing prodrug accumulation and activation in the liver and exerting highly effective and low-toxicity therapeutic effects on HCC. First, PEGylated liposomal cyclophosphamide was prepared by solvent injection and characterized. Importantly, preinjection of PEG-L induced the ABC phenomenon and activation of CYP3A in both HCC rats and HCC mice by studying the effects of repeated injections of PEG-L on pharmacokinetics and tissue distribution. Next, the efficacy and toxicity of repeated injections of PEG-L in HCC mice were examined, and our data indicate that repeated injections are administered in a manner that significantly enhances the antitumor effect compared with controls, with little or no toxicity to other organs. To further reveal the pharmacokinetic mechanism of PEG-L repeated administration for the treatment of HCC, the protein expression of hepatic CYP3A and the concentration of cyclophosphamide in the liver and spleen of HCC mice by inhibiting CYP3A were analyzed. These results revealed that inducing CYP3A to accelerate the rapid conversion of prodrugs that accumulate significantly in the liver is a key mechanism for the treatment of HCC with repeated injections of PEG-L. Collectively, this work taps into the application potential of the ABC phenomenon and provides new insights into the clinical application of PEGylated nanoformulations.
研究领域:
药理学
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肿瘤学
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纳米医学
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药物递送系统
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DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2024
·
IF 4.8
Sun Chen,Zhang Mingyu,Guan Chunjing,Li Weiwei,Peng Ying,Zheng Jiang
Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N -acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat & human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6’ of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10–400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.
研究领域:
药理学
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毒理学
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药物代谢
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DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2023
·
IF 3.8
Xin Xu,Xi-yang Sun,Ming Chang,Zhao-liang Hu,Ting-ting Cheng,Tai-jun Hang,Min Song
Context Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine’s active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD’s major components remains unclear.Objective This study evaluates the herb–drug interaction between DBD’s major components and gemcitabine and validates the underlying pharmacokinetic mechanism.Materials and methods The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis.Results The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD’s major components in rats. The Cmax and AUC of calycosin-7-O-β-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression.Discussion and conclusions Gemcitabine could modulate the pharmacokinetics of DBD’s major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.
研究领域:
肿瘤学
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药理学
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中医
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药代动力学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 6
·718
·
IF 6.9
Kai-Juan Cao,Long Fu,Yu-Chen Sun,Jian Meng,Qin Huang,De-Cheng Deng,Hai-Tang Hu,Zhi-Hui Han,Gang Guo,Xue Zhou,Xiao-Yan Chen
Background/Objectives: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker (P-CAB) used for the treatment of gastroesophageal reflux disease (GERD). To date, its metabolic pathways and metabolism-related drug–drug interactions (DDIs) in humans remain incompletely elucidated. This study aimed to determine the relative contributions (fm) of cytochrome P450 isoforms to JP-1366 elimination and assess its DDI potential.Methods/Results: In vitro metabolic studies using human liver microsomes (HLMs) revealed that JP-1366 was first metabolized to M1, which subsequently underwent further oxidation, glucuronidation, andN-dealkylation. Mono-oxidation was estimated to contribute more than 46% to the overall metabolic clearance of JP-1366. Reaction phenotyping identified CYP3A as the major enzyme (fm= 96.1%), followed by CYP1A2 (1.49%) and CYP2C9 (2.41%). By integrating in vitro data, clinical pharmacokinetic data and clarithromycin coadministration DDI data, a physiologically based pharmacokinetic (PBPK) model was developed and validated. Simulations predicted significant DDIs with strong CYP3A inhibitor (ketoconazole), with AUC ratios of 3.80. Moderate inhibitors (fluconazole and fluvoxamine) caused mild increases (AUC ratios: 1.14–1.74). Conversely, strong and moderate CYP3A inducers, rifampicin and efavirenz, produced pronounced DDIs, with AUC ratios of 0.22 and 0.50, respectively. Furthermore, simulations predicted that although JP-1366 functions as a CYP enzyme inhibitor, it would not cause clinically meaningful changes in the plasma exposure of corresponding CYP substrate drugs; however, potential interactions with CYP3A substrates still warranted consideration.Conclusions: JP-1366 is predominantly cleared via a CYP3A-dominated metabolic pathway. The PBPK simulations suggest that JP-1366 may be a moderately sensitive CYP3A substrate and a moderate inhibitor of sensitive CYP3A substrates, while its perpetrator DDI risk toward other major CYP pathways appears limited. These findings support caution or monitoring when JP-1366 is co-administered with strong CYP3A modulators or sensitive CYP3A substrates.
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高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2026
·
IF 3.2
Yanjie Zhai,Lingwen Dong,Xialing Hao,Xin Li,Weiwei Li,Zixia Hu,Ying Peng,Jiang Zheng
Diaveridine (DVD) is an anticoccidial drug and antibacterial synergist used in the livestock and poultry industries worldwide. DVD residues have been reportedly detected in pork and related meat products. Human exposure to DVD through the environment and the food chain has attracted wide attention, due to the abuse of DVD. Liver injury of animals administered with DVD has been observed and reported, but the potential mechanisms are unelucidated so far. This study aimed to reveal the metabolic activation pathway of DVD that may be related to its hepatotoxicity. DVD was found to be metabolized to an electrophilic species reactive to nucleophilic sulfhydryl groups of cysteine, glutathione (GSH), and N -acetylcysteine (NAC) to generate the cysteine, GSH, and NAC conjugates correspondingly. The GSH conjugates and NAC conjugate(s) were detected in the bile and urine of mice administered with DVD. Furthermore, cysteine conjugates were observed in proteolytic mixture of hepatic proteins obtained from DVD-administered mice in a dose-dependent pattern. CYP3A4 was found to mediate the metabolism of DVD, and an iminoquinone methide intermediate reactive to sulfhydryl of GSH was observed in vitro and in vivo . The GSH conjugates were also detected in primary mouse hepatocytes after exposure to DVD. Pretreatment with ketoconazole (an inhibitor of CYP3A) decreased the formation of the GSH conjugates, and the cytotoxicity associated with DVD was mitigated. This study suggests that DVD was metabolized to the corresponding iminoquinone methide intermediate possibly associated with the hepatotoxicity induced by DVD. This finding facilitates the risk assessment strategies for DVD in food safety supervision.
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高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
·
2023
·Vol. 44
·期 2
·165-174
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IF 2.1
Xuyi Zhan,Shaoyin Bao,Xumei Li,Shaojun Zhou,Maha Raja Dahar,Nengming Lin,Xiugui Chen,Chengshan Niu,Kaige Ji,Yusheng Wu,Kui Zeng,Zhihua Tang,Lushan Yu
Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C max ) compared with the osimertinib in rats and human body.
研究领域:
药理学
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肿瘤学
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生物化学
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PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2026
·
IF 3.6
Jie Dai,Yufen Liao,Xueqian Cheng,Qing Zhang,Tingmin Ye,Dandan Yang,Chunlei Zhang,Ying Peng,Weiwei Li,Jiang Zheng
Tinospora sagittata is a widely used medicinal herb whose safety has raised increasing concerns in recent years. Fibleucin (FBL), a furanoditerpenoid isolated from Tinospora sagittata , has not been systematically evaluated for its safety and toxicological mechanisms despite its presence as a major bioactive constituent in this medicinal plant. To address this toxicological knowledge gap, we comprehensively investigated the hepatotoxicity and/or metabolic activation of FBL in vivo (mice) and in vitro (mouse and human liver microsomal incubations as well as primary mouse hepatocytes). Oral administration of FBL (single intragastric dose) dose-dependently elevated serum ALT, AST, ALP, blood ammonia, and total bile acid levels in mice, accompanied by hepatocellular degeneration, necrosis, and inflammatory infiltration. Pretreatment with the CYP3A inhibitor ketoconazole (100 mg/kg) markedly alleviated the liver injury induced by FBL. LC-MS/MS analysis of mouse liver microsomal incubations and primary hepatocyte exposure (1.0–50 μM FBL) revealed that FBL was bioactivated to an electrophilic intermediate reactive to thiols and amines. Similar observation was obtained in human liver microsomal incubations. The reactive intermediate was found to react with nucleophilic sites of hepatic glutathione and proteins to form the corresponding conjugates and adducts. The observed adduction correlated with the liver injury and cytotoxicity induced by FBL. Chemical synthesis was carried out to probe the mechanism of toxic action. The mechanistic investigation suggests that FBL was metabolized to the corresponding cis -2-butene-1,4-dial intermediate responsible for the GSH depletion and protein adduction.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Yuanyuan Chai,Yunxia Xu,Ziyin Xia,Xin Huang,Luyong Zhang,Zhenzhou Jiang
Ethnopharmacological relevance Zhuanggu Guanjie Pill (ZGGJP), a modern Chinese medicine formula, is composed of 12 herbs and has been used to treat osteoporosis in China for almost 30 years. However, no in vivo study of the influences of ZGGJP on the cytochrome P450 (CYP) activities have been reported. Aim of the study The aim of this study was to evaluate the effects of ZGGJP on the activities and the mRNA expression of CYP enzymes (CYP1A2, CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 and CYP3A) and their corresponding nuclear receptor levels in rats. Materials and methods After 7 days oral treatment of ZGGJP at low- and high-dose, cocktail solution was given to rats. Blood samples were collected at series of time points. The plasma concentrations of probe drugs and their corresponding metabolites were determined by UPLC-MS/MS. The influence of ZGGJP on the activities of seven CYPs were evaluated the metabolic ratios (C max and AUC 0-t) for metabolites/probe drugs. In addition, the effects of ZGGJP on the mRNA expression of CYPs and their corresponding nuclear receptors in rat liver were evaluated by real-time PCR. Results ZGGJP showed significant inductive effects on CYP1A2 and CYP2B6 of both male and female rats. The influence of ZGGJP on CYP2C9 and CYP3A showed gender difference. ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but have no influence on the activities in male rats. ZGGJP had no effects on CYP2D6, CYP2C19 and CYP2E1. The mRNA expression results of CYPs were in accordance with the pharmacokinetic results. The mRNA expression levels of constitutive androstane receptor (CAR) and vitamin D receptor (VDR) were increased significantly in female rats at high dosage, but no significant changes were observed in male rats. Conclusion ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.
研究领域:
民族药理学
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药物代谢
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分子生物学
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Yufen Liao,Xin Wang,Guangyun Ran,Shiyu Zhang,Chutian Wu,Rong Tan,Ying Liu,Yan He,Ting Liu,Zhongxiu Wu,Ying Peng,Weiwei Li,Jiang Zheng
Columbin (CLB) is the most abundant (>1.0%) furan-containing diterpenoid lactone in herbal medicine Tinospora sagittate (Oliv.) Gagnep. The furano-terpenoid was found to be hepatotoxic, but the exact mechanisms remain unknown. The present study demonstrated that administration of CLB at 50 mg/kg induced hepatotoxicity, DNA damage and up-regulation of PARP-1 in vivo . Exposure to CLB (10 μM) induced GSH depletion, over-production of ROS , DNA damage, up-regulation of PARP-1 and cell death in cultured mouse primary hepatocytes in vitro . Co-treatment of mouse primary hepatocytes with ketoconazole (10 μM) or glutathione ethyl ester (200 μM) attenuated the GSH depletion, over-production of ROS, DNA damage, up-regulation of PARP-1, and cell death induced by CLB, while co-exposure to L -buthionine sulfoximine (BSO, 1000 μM) intensified such adverse effects resulting from CLB exposure. These results suggest that the metabolic activation of CLB by CYP3A resulted in the depletion of GSH and increase of ROS formation. The resultant over-production of ROS subsequently disrupted the DNA integrity and up-regulated the expression of PARP-1 in response to DNA damage, and ROS-induced DNA damage was involved in the hepatotoxicity of CLB.
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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细胞生物学
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Qi Luo,Yang Shen,Guohong Zhai,Lin Chen,Furong Ou,Luxi Yi,Danli Yang,Hong Pan,Fuguo Shi
Dictamnine is a representative furan-containing hepatotoxic compound. Administration of dictamnine caused acute liver injury in mice and the metabolic activation of furan to reactive epoxy intermediate was responsible for the hepatotoxicity. This study aimed to characterize the protein adduction by endogenous hepatic aldehydes and investigate its role in dictamnine-induced hepatotoxicity. In the liver sample of dictamnine-treated mice, the protein adduction by five aldehydes was characterized as lysine residue-aldehyde adducts using high-resolution UPLC-Q/Orbitrap MS after exhaustive proteolytic digestion. The levels of protein adduct were increased at 2–3 h after the treatment with dictamnine. The formation of protein adduction increased with increasing doses of dictamnine. Inhibition of the bioactivation by CYP3A inhibitor ketoconazole prevented the protein adduction. Treatment with 2,3-dihydro-dictamnine, an analog of dictamnine that was unable to form the epoxy intermediate, did not lead to an increase in protein adduction. Application of aldehyde dehydrogenase-2 activator ALDA-1 or nucleophilic trapping reagent N -acetyl-L-lysine significantly reduced the protein adduction and attenuated dictamnine-induced liver injury without affecting the bioactivation. In conclusion, the metabolic activation of the furan ring of dictamnine resulted in the protein adduction by multiple hepatic aldehydes and the protein modification played a crucial role in dictamnine-induced liver injury.
研究领域:
药理学
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毒理学
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肝病学
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PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2016
·Vol. 44
·期 4
·607-615
·
IF 3.21
Kai Wang,Hui Wang,Ying Peng,Jiang Zheng
Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.
研究领域:
药理学
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毒理学
·
药物代谢
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2017
·Vol. 45
·期 12
·1354-1363
·
IF 4.242
Hui Wang,Ying Peng,Tingjian Zhang,Qunsheng Lan,Huimin Zhao,Wenbao Wang,Yufei Zhao,Xu Wang,Jianxin Pang,Shaojie Wang,Jiang Zheng
Benzbromarone (BBR) is effective in the treatment of gout; however, clinical findings have shown it can also cause fatal hepatic failure. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) that reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives, fluorinated BBR (6-F-BBR), chlorinated BBR (6-Cl-BBR), and brominated BBR (6-Br-BBR), to decrease the potential for cytochrome P450–mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that 6-F-BBR achieved favorable uricosuric effect, while 6-Cl-BBR and 6-Br-BBR showed weak uricosuric efficacy. Additionally, 6-F-BBR elicited much lower hepatotoxicity in mice. Fluorination of BBR offered advantage to metabolic stability in liver microsomes, almost completely blocked the formation of epoxide metabolite(s) and protein covalent binding, and attenuated hepatic and plasma glutathione depletion. Moreover, the structural manipulation did not alter the efficacy of BBR. This work provided solid evidence that the formation of the epoxide(s) is a key step in the development of BBR-induced hepatotoxicity.
研究领域:
药理学
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毒理学
·
药物化学
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PubMed
高影响因子
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