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Drug Design, Development and Therapy 2021Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell...
PURPOSE
Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of avitinib on cytochrome CYP450 enzymes metabolic activity.
METHODS
A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program.
RESULTS
In vitro experiments revealed different inhibitory effects of avitinib on the six probe substrates with various IC values (bupropion, 6.39/22.64 μM; phenacetin, 15.79/48.36 μM; chlorzoxazone, 23.15/57.09 μM; midazolam, 27.64/59.6 μM; tolbutamide, 42.18/6.91 μM; dextromethorphan, 44.39/56.57 μM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences ( <0.05) in distinct pharmacokinetic parameters (AUC, AUC , C, MRT, MRT , and CLz/F) for the six probe substrates after avitinib pretreatment.
CONCLUSION
A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.
Topics: Animals; Area Under Curve; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Inhibitory Concentration 50; Male; Microsomes, Liver; Pharmaceutical Preparations; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 34456561
DOI: 10.2147/DDDT.S323186 -
Materials (Basel, Switzerland) Jan 2024Acetaminophen (CHNO, also called paracetamol) is an active metabolite of phenacetin with antipyretic and analgesic effects and has been extensively used as a painkiller....
Acetaminophen (CHNO, also called paracetamol) is an active metabolite of phenacetin with antipyretic and analgesic effects and has been extensively used as a painkiller. Currently, the problem of pharmaceuticals in water and sewage is common, especially in highly urbanized countries. Laboratory-scale experiments were carried out using an adsorbent-granulated activated carbon (WD-extra)-to remove acetaminophen (ACT) from water. The initial concentration of acetaminophen was 20 mg ACT/dm. The adsorption kinetics, influence of the pH on adsorption and dose of the used adsorbent were determined under batch conditions. The adsorption of ACT on activated carbon was more efficient when the water solution was acidic (at pH 2, it was the most effective). The highest percentage of removal (99%) was obtained for the WD-extra dose of 10.0 g/dm. The time taken to establish the dynamic equilibrium of the system was 60 min. The effectiveness of adsorption was determined based on the Freundlich and Langmuir adsorption isotherms. It was found that WD-extra activated carbon effectively removed ACT from water solutions.
PubMed: 38255599
DOI: 10.3390/ma17020431 -
Chemosphere Jan 2021Cobalt doped iron oxychloride (Co-FeOCl) was synthesized and employed as catalyst in Fenton degradation of paracetamol (APAP) and phenacetin (PNCT) for the first time....
Cobalt doped iron oxychloride (Co-FeOCl) was synthesized and employed as catalyst in Fenton degradation of paracetamol (APAP) and phenacetin (PNCT) for the first time. The catalytic performance was evaluated by means of various parameters including catalyst load, hydrogen peroxide (HO) dose and pH value. The high removal of APAP (87.5%) and PNCT (76.0%) was obtained under conditions of 0.2 g/L Co-FeOCl and 0.5 mM HO at pH 7.0, with calculated pseudo-first order kinetic constants of 0.031 min for APAP and 0.023 min for PNCT. Particularly, quenching tests and in situ electron spin resonance (ESR) tests were employed for the identification of the reactive oxygen species (ROS) in system. Hydroxyl radical (·OH) and superoxide radical (O·) were the primary ROS in Co-FeOCl/HO system. A possible mechanism for HO activation by Co-FeOCl catalyst was proposed as well. Finally, the formation of typical disinfection by-products (DBPs) decreased slightly in Co-FeOCl/HO pre-oxidation. However, stability and reusability of Co-FeOCl were deactivated in the consecutive three cycles.
Topics: Acetaminophen; Catalysis; Cobalt; Hydrogen Peroxide; Iron Compounds; Oxidation-Reduction; Phenacetin
PubMed: 33297032
DOI: 10.1016/j.chemosphere.2020.127989 -
Frontiers in Cell and Developmental... 2021Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor....
Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset ( = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset ( = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. The FRGPI was established based on the , , , and genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4 T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4 T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.
PubMed: 35174170
DOI: 10.3389/fcell.2021.812422 -
Current Drug Metabolism Dec 2022The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have...
BACKGROUND
The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have been reported. Since Cytochrome P450 (CYP) enzymes play an important role in drug interactions. The evaluation of the influence of herbal medicines on the activities of CYPs is beneficial to promote scientific and rational clinical use of herbal medicines.
OBJECTIVE
Herein, we aimed to develop and validate a method to simultaneously quantify seven CYP cocktail probe drugs consisting of phenacetin (PNC), bupropion (BPP), losartan potassium (LK), omeprazole (OMP), dextromethorphan (DM), chlorzoxazone (CZZ) and midazolam (MDZ) and their respective metabolites in a single acquisition run and use this method to evaluate the influence of Zhuanggu Guanjie Pill (ZGGJP) on seven CYPs.
METHODS
A cost-effective and simple UHPLC-(±)ESI-MS/MS method for simultaneous determination of seven probe drugs and metabolites in rat plasma was developed and validated. Male and female rats were randomly divided into three groups and treated with 1.2 g/kg/d ZGGJP, 5 g/kg/d ZGGJP and 0.5% CMC-Na for 14 consecutive days. After 24 h of the last administration, all rats were administrated orally with probe drugs. The influence of ZGGJP on the CYPs was carried out by comparing the metabolic ratio (Cmax, AUC0-t) of metabolites/probe drugs in rats.
RESULTS
The calibration curves were linear, with correlation coefficient > 0.99 for seven probe drugs and their corresponding metabolites. Intra- and inter-day precisions were not greater than 15% RSD and the accuracies were within ±15% of nominal concentrations. The ZGGJP showed significant inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.
CONCLUSION
ZGGJP had inductive effects on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.
PubMed: 36503399
DOI: 10.2174/1389200224666221209154002 -
Frontiers in Microbiology 2022Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on...
Unravelling the pharmacokinetics of aflatoxin B1: determination of Michaelis-Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes.
Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on the human body. The phase I metabolism in the human liver, performed by cytochrome P450 (CYP450) enzymes, is accountable for more than 80% of the overall metabolism of exogenous and endogenous compounds. Mycotoxins are (partially) metabolized by CYP450 enzymes. In this study, research was performed on CYP450 probes and aflatoxin B1 (AFB1), a carcinogenic mycotoxin, to obtain pharmacokinetic data on AFB1, required for further experimental work. The CYP450 probes of choice were a CYP3A4 substrate, midazolam (MDZ) and a CYP1A2 substrate, phenacetin (PH) since these are the main metabolizing phase I enzymes of AFB1. Linearity experiments were performed on the three substrates indicating that linear conditions were achieved at a microsomal protein concentration and incubation time of 0.25 mg/ml and 5 min, 0.50 mg/ml and 20 min and 0.25 mg/ml and 5 min for MDZ, PH and AFB1, respectively. The was determined in human liver microsomes and was estimated at 2.15 μM for MDZ, 40.0 μM for PH and 40.9 μM for AFB1. The associated values were 956 pmol/(mg.min) (MDZ), 856 pmol/(mg.min) (PH) and 11,536 pmol/(mg.min) (AFB1). Recombinant CYP systems were used to determine CYP450-specific Michaelis-Menten values for AFB1, leading to a CYP3A4 of 49.6 μM and an intersystem extrapolation factor (ISEF) corrected of 43.6 pmol/min/pmol P450 and a CYP1A2 of 58.2 μM and an ISEF corrected of 283 pmol/min/pmol P450. An activity adjustment factor (AAF) was calculated to account for differences between microsome batches and was used as a correction factor in the determination of the human hepatic clearance for MDZ, PH and AFB1. The hepatic blood clearance corrected for the AAF CL, CL CL and CL were determined in HLM at 44.1 L/h, 21.7 L/h, 40.0 L/h and 38.5 L/h. Finally, inhibition assays in HLM showed that 45% of the AFB1 metabolism was performed by CYP3A4/3A5 enzymes and 49% by CYP1A2 enzymes.
PubMed: 36110298
DOI: 10.3389/fmicb.2022.988083 -
Journal of Analytical Toxicology Jul 2022Toxic adulterants are drug or chemical agents used to add bulk volume to traditional drugs of abuse such as cocaine and heroin. These cutting agents include levamisole,...
Toxic adulterants are drug or chemical agents used to add bulk volume to traditional drugs of abuse such as cocaine and heroin. These cutting agents include levamisole, metamizole, noxiptillin, phenacetin and xylazine as well as common legal drugs such as acetaminophen, caffeine, diphenhydramine, lidocaine, quinine, quetiapine and tramadol. Because they possess pharmacological activity they result in exposure of the user, but also in the case of pregnant women, the developing fetus, to potential drug toxicity. We describe the development, validation and implementation of a rapid (48 second sample-to-sample) test based on a qualitative data-dependent liquid chromatography-quadrupole time of flight mass spectrometry method for the analysis of toxic adulterating substances in umbilical cord tissue (UCT) samples. The method provides a means of studying potential in utero exposure to these agents. Library spectra comparison at three different collision energies was used in conjunction with retention time and accurate mass to identify these substances in UCT. Analytically based reporting limits were established to determine positivity rates of adulterants in UCT utilizing a standard addition approach. The method was applied to authentic cocaine and opioid positive UCT to screen for toxic adulterants. There were a total of 82 potential adulterant positives found in a 30-sample cohort of authentic UCT samples, with an average of 2.7 substances per case. Lidocaine was the predominant finding followed by caffeine, and diphenhydramine all of which could result from non-illicit drug exposure, however, there were positives for levamisole, phenacetin, noxiptillin and xylazine none of which are approved in the United States for human therapeutic use. This initial set of data established a preliminary positivity rate of potentially toxic adulterants in UCT samples positive for cocaine or opioid use.
Topics: Analgesics, Opioid; Caffeine; Cocaine; Diphenhydramine; Drug Contamination; Female; Humans; Levamisole; Lidocaine; Phenacetin; Pregnancy; Umbilical Cord; Xylazine
PubMed: 34592760
DOI: 10.1093/jat/bkab094 -
Ecotoxicology and Environmental Safety Nov 2020Indirect oxidation induced by reactive free radicals, such as hydroxyl radical (HO), sulfate radical (SO) and carbonate radical (CO), plays an important or even crucial...
Indirect oxidation induced by reactive free radicals, such as hydroxyl radical (HO), sulfate radical (SO) and carbonate radical (CO), plays an important or even crucial role in the degradation of micropollutants. Thus, the coadjutant degradation of phenacetin (PNT) by HO, SO and CO, as well as the synergistic effect of O on HO and HO were studied through mechanism, kinetics and toxicity evaluation. The results showed that the degradation of PNT was mainly caused by radical adduct formation (RAF) reaction (69% for Г, the same as below) and H atom transfer (HAT) reaction (31%) of HO. For the two inorganic anionic radicals, SO initiated PNT degradation by sequential radical addition-elimination (SRAE; 55%), HAT (28%) and single electron transfer (SET; 17%) reactions, while only by HAT reaction for CO. The total initial reaction rate constants of PNT by three radicals were in the order: SO > HO > CO. The kinetics of PNT degradation simulated by Kintecus program showed that UV/persulfate could degrade target compound more effectively than UV/HO in ultrapure water. In the subsequent reaction of PNT with O, HO and HO, the formation of mono/di/tri-hydroxyl substitutions and unsaturated aldehydes/ketones/alcohols were confirmed. The results of toxicity assessment showed that the acute and chronic toxicity of most products to fish increased and to daphnia decreased, and acute toxicity to green algae decreased while chronic toxicity increased.
Topics: Animals; Carbonates; Chlorophyta; Daphnia; Fishes; Hydrogen Peroxide; Ions; Kinetics; Models, Chemical; Oxygen; Phenacetin; Sulfates; Toxicity Tests, Acute; Toxicity Tests, Chronic; Water
PubMed: 32739673
DOI: 10.1016/j.ecoenv.2020.110977 -
Chemical Research in Toxicology Apr 2021Binimetinib is a selective MEK1/2 inhibitor, which is indicative of melanoma. We aimed to investigate the inhibitory effect of binimetinib on cytochrome P450 using human...
Binimetinib is a selective MEK1/2 inhibitor, which is indicative of melanoma. We aimed to investigate the inhibitory effect of binimetinib on cytochrome P450 using human liver microsomes. Binimetinib was demonstrated to display reversible and time-dependent inhibitory effects on human CYP1A2. Binimetinib can inhibit the activity of phenacetin deethylation with IC of 5.6 μM. A 30 min preincubation of binimetinib with NADPH-supplemented human liver microsomes raised a significant left IC shift (6.5-fold), from 5.69-0.88 μM. The inactivation parameters and were 0.063 min and 15.47 μM, and the half-life of inactivation was 11 min. Glutathione (GSH) and catalase/superoxide exhibited minor or no protective effect on binimetinib-induced enzyme inactivation. Trapping experiment by GSH induced a detection of GSH adduct, of which the formation was believed to be through the oxidation of electron-rich 1,4-benzenediamine to reactive 1,4-diiminoquinone species. Cytochrome P450 3A4, 2C9, and 2D6 were involved in the bioactivation of binimetinib. In conclusion, binimetinib was proven to display reversible and time-dependent inhibitory effect on CYP1A2, which may have implications for the toxicity of binimetinib.
Topics: Benzimidazoles; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Humans; Microsomes, Liver; Molecular Structure; Time Factors
PubMed: 33728909
DOI: 10.1021/acs.chemrestox.1c00036 -
IUCrJ May 2021As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to...
As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to investigate the relationship between the solvent and nucleation kinetics. Induction times at different supersaturation in six solvents were measured. FTIR and NMR spectroscopy were employed to explore the solvent-solute interactions and the self-association properties in solution. Density functional theory (DFT) was adopted to evaluate the strength of solute-solvent interactions and the molecular conformations in different solvents. Based on these spectroscopy data, molecular simulation and nucleation kinetic results, a comprehensive understanding of the relationship between molecular structure, crystal structure, solution chemistry and nucleation dynamics is discussed. Both the solute-solvent interaction strength and the supramolecular structure formed by the self-association of solute molecules affect the nucleation rate. The findings reported here shed new light on the molecular mechanism of nucleation in solution.
PubMed: 33953933
DOI: 10.1107/S2052252521003882