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1.
J Toxicol Sci ; 47(5): 193-199, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35527007

RESUMO

According to ICH S3A Q&A focusing on microsampling, its application should be avoided in main study animals for test drugs that could exacerbate hematological parameters with frequent blood sampling. However, no study has reported the effects of microsampling on toxicity parameters of drugs known to induce hematological toxicity. Therefore, we assessed the toxicological effects of serial microsampling on rats treated with phenacetin as a model drug. In a common 28-day study, 50 µL of microsampling was performed at 6-time points on days 1 to 2 and 7-time points on days 27 to 28 from the jugular vein of Sprague Dawley rats. The study was performed independently by two organizations. The toxicological influence of microsampling was evaluated on body weight, food consumption, hematology, blood clinical chemistry, urine parameters, organ weights, and tissue pathology. Phenacetin treatments induced significant changes of various hematological parameters (including hemoglobin and reticulocytes), some organ weights (including liver and spleen), and some hematology-related pathological parameters in the liver, spleen and bone marrow. Meanwhile, serial microsampling exhibited minimal influence on the assessed parameters, although 20 parameters showed statistical differences mostly at one organization. The current results support the notion that serial 50 µL microsampling from the jugular vein had minimal impacts on overall toxicological profiles even in rats treated with a drug inducing hematological toxicity, but the potential adverse effect on certain parameters could not be fully excluded. Accordingly, this microsampling technique has possibility to be employed even for non-clinical rat toxicity studies using drugs with potentially hematological toxicity.


Assuntos
Coleta de Amostras Sanguíneas , Fenacetina , Animais , Coleta de Amostras Sanguíneas/métodos , Peso Corporal , Veias Jugulares , Fenacetina/toxicidade , Ratos , Ratos Sprague-Dawley , Baço
2.
Chem Asian J ; 17(6): e202101372, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35018742

RESUMO

SnO2 -CNF was prepared by coaxial blending technology, and MoS2 was grown uniformly on SnO2 -CNF composite by adding a hydrothermal post-treatment step. The uniform distribution of MoS2 on one-dimensional SnO2 -CNF can effectively establish a layered three-dimensional structure. Accordingly, the prepared MoS2 -coated SnO2 -CNF composite material has higher surface area and more active sites to obtain better electrochemical performance. We constructed an electrochemical sensor within the composite material with enhanced performance to realize the simultaneous and highly sensitive detection of phenacetin and indomethacin. The sensor has linear ranges of 0.050-7200 µM and 0.05-500 µM, respectively, and the detection limits were 0.016 µM and 0.013 µM. Furthermore, the sensor has good anti-interference ability and stability, which also achieves good recovery rate in the actual sample detection.


Assuntos
Carbono , Nanofibras , Carbono/química , Técnicas Eletroquímicas/métodos , Indometacina , Molibdênio , Nanofibras/química , Fenacetina
3.
Eur J Drug Metab Pharmacokinet ; 47(2): 177-185, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34881402

RESUMO

BACKGROUND AND OBJECTIVES: Atemoya (Annona atemoya) is increasingly being consumed worldwide because of its pleasant taste. However, only limited information is available concerning possible atemoya-drug interactions. In the present study, the issue of whether atemoya shows food-drug interactions with substrate drugs of the major drug-metabolizing cytochrome P450s (i.e., CYP1A2, CYP2C9, and CYP3A) is addressed. METHODS: The ability of atemoya juice to inhibit the activities of phenacetin O-deethylase (CYP1A2), diclofenac 4'-hydroxylase (CYP2C9), and midazolam 1'-hydroxylase (CYP3A) was examined in vitro using human and rat liver microsomes. The in vivo pharmacokinetics of phenacetin and metabolites derived from it in rats when atemoya juice or fluvoxamine (a CYP1A2 inhibitor) was preadministered were also investigated. RESULTS: Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A. In spite of this inhibition, preadministration of atemoya had no effect on the pharmacokinetics of phenacetin, a CYP1A2 substrate, in rats. Meanwhile, preadministration of fluvoxamine significantly extended the time needed for the elimination of phenacetin, possibly due to the inhibition of CYP1A2. This suggests that the intake of an excess amount of atemoya juice is necessary to cause a change in the pharmacokinetics of phenacetin when the IC50 values for CYP1A2 inhibition by atemoya and fluvoxamine are taken into account. CONCLUSION: The results indicate that a daily intake of atemoya would not change the pharmacokinetics of CYP1A2 substrates such as phenacetin as well as CYP2C9- and CYP3A-substrate drugs.


Assuntos
Annona , Animais , Annona/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Interações Alimento-Droga , Frutas , Microssomos Hepáticos/metabolismo , Fenacetina , Ratos
4.
Toxicol Lett ; 356: 33-40, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34896239

RESUMO

Three plasticizers, namely bis (3,5,5-trimethylhexyl) phosphate (TMHPh), di(propylene glycol) dibenzoate (DiPGDB), and tri-n-butyl trimellitate (TBTM), were recently identified and reported in high concentrations in indoor dust from Belgian homes. In this study, their behavior within the human body was investigated by generating Phase I biotransformation products for the first time. Human liver microsomes (HLMs) were used following an in vitro assay and liquid chromatography time of flight mass spectrometry (LC-QTOF-MS) was employed for the analysis. Biotransformation products were identified for TMHPh as products of hydroxylation reactions that took place in one or two positions in the structure of the substrate. For DiPGDB, biotransformation products were formed after hydrolysis of carboxylic esters and oxidative-O-dealkylation. For TBTM, biotransformation products were formed through hydrolysis of the different carboxylic esters of the molecule, in agreement with studies on structurally similar compounds. The generated results can contribute to biomonitoring studies creating new knowledge on human exposure to emerging compounds and on the metabolism of xenobiotics.


Assuntos
Espectrometria de Massas/métodos , Microssomos Hepáticos/metabolismo , Plastificantes/metabolismo , Monitoramento Biológico , Poeira/análise , Humanos , Estrutura Molecular , Fenacetina/metabolismo , Plastificantes/química
5.
Sci Total Environ ; 803: 150068, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34525735

RESUMO

Phenacetin (PNCT), a common antipyretic and analgesic drug, is often used to treat fever and headache. However, the effect of PNCT on nitrifiers in wastewater treatment processes remains unclear. The practicability of attaining partial nitrification (PN) through inhibitor-PNCT was investigated in this study. The optimal treatment conditions of soaking once for 18 h with 2.50 × 10-3 g PNCT/(g MLSS) were applied to the PN stability experiment. The results showed that ammonia oxidation activity recovered quickly after 3 cycles of operation, while nitrite oxidation activity was suppressed steadily. In addition, average ammonium removal efficiency and nitrite accumulation ratio during 138 cycles could reach 94.94% and 85.38%, respectively. Complimentary DNA high-throughput sequencing and oligotyping analysis showed that the activity of Nitrosomonas would gradually surpass Nitrospira after PNCT treatment only once. The decrease of Nitrospira activity was accompanied by the simplification of oligotypes after PNCT treatment, while Nitrosomonas could adapt to PNCT stress by reducing the differences between oligotypes. Metagenomics revealed that the decrease in the number of NXR in the nitrogen metabolism pathways was the key reason for achieving PN. The potential mechanisms might be that the dominant nitrite-oxidizing bacteria and complete ammonia oxidizers were bio-killed by PNCT.


Assuntos
Metagenômica , Fenacetina , Amônia , Reatores Biológicos , Nitrificação , Nitritos , Nitrogênio , Oxirredução
6.
Analyst ; 146(20): 6228-6238, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34528034

RESUMO

We have developed a sensitive and rapid gold nanoparticle-based immunochromatographic strip (GNP-ICS) for the detection of phenacetin (PNCT) and paracetamol (PAP) using an anti-PNCT monoclonal antibody (mAb). The sensitive anti-PNCT mAb (2D6) had a half maximal inhibitory concentration (IC50) and limit of detection (LOD) of 3.51 and 0.21 ng mL-1, respectively. Additionally, its cross-reactivity with PAP was approximately 10.1%. The developed GNP-ICS assay based on GNP-labeled mAb was sensitive for the detection of PNCT with vLOD and cut-off values of 2.5 and 50 ng mL-1 respectively and a vLOD value of 25 ng mL-1 for PAP. Furthermore, the developed icELISA and GNP-ICS assays were applied to determine PNCT-spiked beverage samples without pretreatment, in addition to a kind of PAP-containing drug. The recoveries were validated using high performance liquid chromatography (HPLC). The results revealed that the developed GNP-ICS assay was reliable for the detection of PNCT in practical samples.


Assuntos
Ouro , Nanopartículas Metálicas , Acetaminofen , Cromatografia de Afinidade , Ensaio de Imunoadsorção Enzimática , Limite de Detecção , Fenacetina
7.
Forensic Sci Int ; 327: 110911, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34450541

RESUMO

Cocaine is a naturally occurring psychostimulant drug available worldwide. Drug trafficking networks adulterate pure cocaine with cutting agents to increase their earnings. This study presents a descriptive statistical analysis of the cutting agents found in 2118 cocaine samples that were seized in the Northern Region of Colombia (in the period 2015-2017). The data used in this study was drawn from the GC-MS analytical reports of the National Institute of Legal Medicine and Forensic Sciences -Colombia, Northern Region. Results showed diverse cutting agents in seized cocaine samples, from which the most commonly used are caffeine, phenacetin, lidocaine, imidazole and levamisole. In addition, cocaine samples showed different mixtures of the above cutting agents, predominantly caffeine/phenacetin and caffeine/lidocaine/phenacetin mixtures.


Assuntos
Cocaína/química , Contaminação de Medicamentos , Tráfico de Drogas/tendências , Aporfinas/análise , Cafeína/análise , Codeína/análise , Colômbia , Humanos , Imidazóis/análise , Levamisol/análise , Lidocaína/análise , Fenacetina/análise , Análise Espaço-Temporal , Tetramizol/análise
8.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279418

RESUMO

The thermodynamic properties of phenacetin in solid state and in saturated conditions in neat and binary solvents were characterized based on differential scanning calorimetry and spectroscopic solubility measurements. The temperature-related heat capacity values measured for both the solid and melt states were provided and used for precise determination of the values for ideal solubility, fusion thermodynamic functions, and activity coefficients in the studied solutions. Factors affecting the accuracy of these values were discussed in terms of various models of specific heat capacity difference for phenacetin in crystal and super-cooled liquid states. It was concluded that different properties have varying sensitivity in relation to the accuracy of heat capacity values. The values of temperature-related excess solubility in aqueous binary mixtures were interpreted using the Jouyban-Acree solubility equation for aqueous binary mixtures of methanol, DMSO, DMF, 1,4-dioxane, and acetonitrile. All binary solvent systems studied exhibited strong positive non-ideal deviations from an algebraic rule of mixing. Additionally, an interesting co-solvency phenomenon was observed with phenacetin solubility in aqueous mixtures with acetonitrile or 1,4-dioxane. The remaining three solvents acted as strong co-solvents.


Assuntos
Fenacetina/química , Solventes/química , Água/química , Fenômenos Físicos , Solubilidade , Temperatura , Termodinâmica
9.
Life Sci ; 277: 119486, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33864822

RESUMO

AIMS: Human carboxylesterases (CESs) and arylacetamide deacetylase (AADAC) are serine-esterase enzymes catalyzing the hydrolysis of many compounds containing esters, amides, thioesters, or acetyl groups. This study aimed to investigate the presence, kinetic parameters, and inhibition of CES1, CES2, and AADAC in A549, H460, and H727 pulmonary cells in both living cells and S9 fractions. MATERIALS AND METHODS: The p-nitrophenyl acetate (pNPA) and 4-methylumbelliferyl acetate (4-MUA) were used as non-selective esterase substrates, whereas phenacetin as selective AADAC substrate. CESs activities were also investigated in living cells by cellular bioimaging using selective fluorescent probes. KEY FINDINGS: AADAC gene was detected in A549 and H460 cells; nevertheless, arylesterase activity was not found in relative S9 fractions. Besides, CES1 and CES2 were expressed to a different extent by all lung cells, and enzymatic activities were quite overlapping each other. All enzymes exhibited a typical Michaelis-Menten saturation curve and, regarding 4-MUA, similar Km values were found in both living cells and S9 fractions. Conversely, kinetic parameters relative to the pNPA hydrolysis by S9 fractions were significantly lower than those detected in living cells. Inhibition studies revealed that 4-MUA hydrolysis was inhibited by bis-p-nitrophenyl phosphate and phenylmethanesulfonyl fluoride more than loperamide; on the contrary, pNPA hydrolysis inhibition was limited with similar inhibition profiles being obtained in both living cells and S9 fractions. The presence of carboxylesterases was definitely confirmed by cellular bioimaging. SIGNIFICANCE: These findings add information to esterase knowledge in pulmonary cells that could be used as in vitro models for toxicological and pharmacological studies.


Assuntos
Carboxilesterase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Células A549 , Carboxilesterase/análise , Hidrolases de Éster Carboxílico/análise , Linhagem Celular , Esterases/metabolismo , Esterases/farmacologia , Humanos , Hidrólise , Pulmão/metabolismo , Microssomos Hepáticos/metabolismo , Nitrofenóis , Fenacetina , Especificidade por Substrato , Umbeliferonas
10.
Chemosphere ; 269: 129337, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33387793

RESUMO

Acetaminophen (ACT) and phenacetin (PNT) removal during light-emitting diode (LED)-UV photolysis of persulfate (PS) was evaluated with a typical wavelength of 365 nm. Decay of PNT and ACT in pH ranges of 5.5-8.5 followed pseudo-first order kinetics. Maximum pseudo-first order rate constants (kobs) of ACT and PNT decomposition of 1.8 × 10-1 and 1.2 × 10-1 min-1, respectively, were obtained at pH 8.5. Hydroxyl radicals (·OH), sulfate radicals (SO4·-), superoxide radicals (O2-·), and singlet oxygen (1O2) were determined in-situ electron paramagnetic resonance (EPR) and alcohol scavenging tests. The average contributions of ·OH and SO4·- were 23.5% and 53.0% for PNT removal, and 15.9% and 53.0% for ACT removal at pH ranges of 5.5-8.5. In samples subjected to chlorination after LED-UV365/PS pre-oxidation, a relatively small total concentration of five halogenated disinfection by-products (DBPs) was obtained of 90.9 µg L-1 (pH 5.5) and 126.7 µg L-1 (pH 7.0), which is 58.5% and 30.2% lower than that in system without LED-UV365/PS pre-oxidation. Meanwhile, a higher maximum value of total DBP concentration was obtained at pH 8.5 (445.6 µg L-1) following LED-UV365/PS pre-oxidation. The results of economy evaluation showed that UV365 was more cost-effective in application for organic contaminant removal compared with UV254.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Acetaminofen , Cinética , Oxirredução , Fenacetina , Fotólise , Espécies Reativas de Oxigênio , Raios Ultravioleta , Poluentes Químicos da Água/análise
11.
Chemosphere ; 263: 127989, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297032

RESUMO

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 (H2O2) 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 H2O2 at pH 7.0, with calculated pseudo-first order kinetic constants of 0.031 min-1 for APAP and 0.023 min-1 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 (O2-·) were the primary ROS in Co-FeOCl/H2O2 system. A possible mechanism for H2O2 activation by Co-FeOCl catalyst was proposed as well. Finally, the formation of typical disinfection by-products (DBPs) decreased slightly in Co-FeOCl/H2O2 pre-oxidation. However, stability and reusability of Co-FeOCl were deactivated in the consecutive three cycles.


Assuntos
Acetaminofen , Peróxido de Hidrogênio , Catálise , Cobalto , Compostos de Ferro , Oxirredução , Fenacetina
12.
J Pharmacol Toxicol Methods ; 106: 106934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33080390

RESUMO

INTRODUCTION: Ex vivo studies of human fetal hepatic drug metabolism are uncommon as it requires access to functional liver tissue and therefore raises practical and ethical concerns. Large animal models provide an alternative opportunity to study changes in cytochrome P450 (CYP) activity in the mother and fetus during pregnancy. We aimed to develop methods to determine the activity of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in sheep hepatic microsomes. METHODS: We identified optimal conditions to determine the activity of CYP1A2 (using the probe drug phenacetin), CYP2C9 (diclofenac), CYP2D6 (dextromethorphan) and CYP3A4 (midazolam) by varying techniques for microsome extraction, probe drug concentration, incubation time and microsome concentration. The specificity of each probe drug was assessed by determining the rate of metabolism when specific CYP enzyme inhibitors were included in the reaction. RESULTS: The optimum incubation time and probe drug concentration was six hours with 5 µM phenacetin (CYP1A2), four hours with 10 µM diclofenac (CYP2C9), 30 min with 1 µM of midazolam (CYP3A4) and 10 min with 1 µM dextromethorphan (CYP2D6). For both CYP2D6 and CYP3A4 reactions required 20 µg of microsomal protein, whereas for CYP1A2 and CYP2C9, reactions required 40 µg of microsomal protein. Metabolism of phenacetin, dextromethorphan and midazolam was reduced by specific enzyme inhibitors, but the specific CYP2C9 inhibitor sulfaphenazole did not substantially inhibit diclofenac metabolism. DISCUSSION: This study identifies the optimal conditions for determining CYP activity in maternal sheep hepatic microsomes. In doing so, we have developed a standardised protocol for assessment of microsomal activity of CYP3A4, CYP1A2 and CYP2D6, but we were unable to optimise conditions for assessment of CYP2C9. This approach can be applied to investigate the impact of pregnancy complications on maternal and fetal hepatic drug metabolism.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Ensaios Enzimáticos/métodos , Microssomos Hepáticos/enzimologia , Complicações na Gravidez/metabolismo , Animais , Fracionamento Celular/métodos , Sistema Enzimático do Citocromo P-450/análise , Dextrometorfano/farmacocinética , Diclofenaco/farmacocinética , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Troca Materno-Fetal , Microssomos Hepáticos/efeitos dos fármacos , Midazolam/farmacocinética , Fenacetina/farmacocinética , Gravidez , Complicações na Gravidez/tratamento farmacológico , Ovinos
13.
Ecotoxicol Environ Saf ; 204: 110977, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739673

RESUMO

Indirect oxidation induced by reactive free radicals, such as hydroxyl radical (HO), sulfate radical (SO4-) and carbonate radical (CO3-), plays an important or even crucial role in the degradation of micropollutants. Thus, the coadjutant degradation of phenacetin (PNT) by HO, SO4- and CO3-, as well as the synergistic effect of O2 on HO and HO2 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, SO4- 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 CO3-. The total initial reaction rate constants of PNT by three radicals were in the order: SO4- > HO > CO3-. The kinetics of PNT degradation simulated by Kintecus program showed that UV/persulfate could degrade target compound more effectively than UV/H2O2 in ultrapure water. In the subsequent reaction of PNT with O2, HO and HO2, 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.


Assuntos
Carbonatos/toxicidade , Peróxido de Hidrogênio/toxicidade , Fenacetina/toxicidade , Sulfatos/toxicidade , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Animais , Carbonatos/química , Clorófitas/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Peixes , Peróxido de Hidrogênio/química , Íons/química , Íons/toxicidade , Cinética , Modelos Químicos , Oxigênio/química , Fenacetina/química , Sulfatos/química , Água/química
14.
Sci Rep ; 10(1): 8828, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483226

RESUMO

High-performance liquid chromatography (HPLC) is the most common analytical method practiced in various fields and used for analysis of almost all drug compounds in the pharmaceutical industries. During drug development, an evaluation of potential drug interaction with cytochrome P450 (CYP) is essential. A "cocktail" approach is often used in drug development to evaluate the effect of a drug candidate on multiple CYP enzymes in a single experiment. So far, simultaneous analysis of multiple CYP substrates, which have greatly different structure and physicochemical properties, has required organic solvents and mobile phase gradient methods. However, despite the recent emphasis on environmental protection, analytical methods that use only aqueous solvents without the use of organic solvents for separation have not been studied well. This study sought to develop the simultaneous analysis of multiple CYP substrates by using poly(N-isopropylacrylamide) (PNIPAAm)-based temperature-responsive chromatography with only aqueous solvents and isocratic methods. Good separation of multiple CYP substrates was achieved without using organic solvents and any gradient methods by temperature-responsive chromatography utilizing a P(NIPAAm-co-n-butyl methacrylate (BMA))- and P(NIPAAm-co-N-acryloyl L-tryptophan methyl ester (L-Trp-OMe))-grafted silica column. Overall, PNIPAAm-based temperature-responsive chromatography represents a remarkably simple, versatile, and environmentally friendly bioanalytical method for CYP substrates and their metabolites.


Assuntos
Resinas Acrílicas/química , Cromatografia Líquida/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Química Verde/métodos , Clorzoxazona/metabolismo , Cumarínicos/metabolismo , Desenvolvimento de Medicamentos , Mefenitoína/metabolismo , Estrutura Molecular , Fenacetina/metabolismo , Solventes , Especificidade por Substrato , Temperatura , Testosterona/metabolismo , Tolbutamida/metabolismo , Água
15.
J Colloid Interface Sci ; 569: 378-385, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32126350

RESUMO

Microcompartments in the form of water-in-oil droplets have been utilized to construct artificial cells and simulate human body environment. However, the performance of subcellular structure involved metabolism in emulsion droplets has not been explored, and the underlying mechanism is still being elucidated. In this work, drug metabolism is presented on the basis of great amounts of microcompartments formed of picoliter-volume droplets with different radius (R), using a commercial four-way valve as a droplet generator. A model substrate, phenacetin, and its metabolite, paracetamol, are quantitatively analyzed by liquid-chromatography (LC) tandem mass spectrometry (MS/MS), and the reaction kinetics is characterized. In microdroplets of varying size (R = 18, 27, 42, and 51 µm, respectively), both conversion ratio and reaction rate constant of the metabolism are influenced in different degree. For instance, the substrate conversion ratio after 60 min of incubation in R = 27 µm droplets improves from 15% to 42%, and the reaction rate constant improves nearly five-fold, compared to that in bulk phase. The influence of microcompartment size on metabolism rate is further explored by simulation using a diffusion-reaction model. The droplet-based strategy is rapid, accurate and cost-efficient, fitting especially into biomimetic metabolism studies.


Assuntos
Acetaminofen/análise , Materiais Biomiméticos/análise , Materiais Biomiméticos/metabolismo , Microesferas , Fenacetina/análise , Fenacetina/metabolismo , Cromatografia Líquida de Alta Pressão , Difusão , Emulsões/química , Cinética , Metaboloma , Modelos Químicos , Óleos/química , Espectrometria de Massas em Tandem , Água/química
16.
Drug Des Devel Ther ; 14: 429-434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099327

RESUMO

BACKGROUND: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. AIM: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. METHODS: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P<0.001). CONCLUSION: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.


Assuntos
Inibidores das Enzimas do Citocromo P-450/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Isoflavonas/metabolismo , Animais , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Isoflavonas/química , Isoflavonas/farmacologia , Medicina Tradicional Chinesa , Metoprolol/química , Metoprolol/metabolismo , Midazolam/química , Midazolam/metabolismo , Omeprazol/química , Omeprazol/metabolismo , Fenacetina/química , Fenacetina/metabolismo , Ratos , Tolbutamida/química , Tolbutamida/metabolismo
17.
Biochemistry (Mosc) ; 85(Suppl 1): S79-S107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087055

RESUMO

The review summarizes the data on the role of metabolic and repair systems in the mechanisms of therapy-related carcinogenesis and the effect of their polymorphism on the cancer development risk. The carcinogenic activity of different types of drugs, from the anticancer agents to analgesics, antipyretics, immunomodulators, hormones, natural remedies, and non-cancer drugs, is described. Possible approaches for the prevention of drug-related cancer induction at the initiation and promotion stages are discussed.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos , Neoplasias/induzido quimicamente , Neoplasias/prevenção & controle , Animais , Antineoplásicos/efeitos adversos , Ácidos Aristolóquicos/efeitos adversos , Arsênio/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Dietilestilbestrol/efeitos adversos , Estrogênios/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Fenacetina/efeitos adversos , Medicina de Precisão , Fatores de Risco
18.
Toxicol Lett ; 319: 155-159, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706005

RESUMO

Novel HepG2 cell clones 1A2 C2 and 1A2 C7 were independently generated by lentiviral transduction to functionally overexpress cytochrome P450 1A2 (CYP1A2). We found similar and stable CYP1A2 transcript and protein levels in both cell clones leading to specific enzyme activities of about 370 pmol paracetamol x min-1 x mg-1 protein analyzed by phenacetin conversion. Both clones showed dramatically increased sensitivity to the hepatotoxic compound aflatoxin B1 (EC50 < 100 nM) when compared to parental HepG2 cells (EC50∼5 µM). Thus, newly established cell lines are an appropriate tool to study metabolism and toxicity of substances depending on conversion by CYP1A2.


Assuntos
Citocromo P-450 CYP1A2/genética , Vetores Genéticos/genética , Hepatoblastoma/enzimologia , Hepatoblastoma/genética , Lentivirus/genética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Aflatoxina B1/toxicidade , Linhagem Celular Tumoral , Citocromo P-450 CYP1A2/biossíntese , Impressões Digitais de DNA/métodos , Humanos , Fígado/metabolismo , Mycoplasma/química , Fenacetina/farmacocinética , Plasmídeos/genética
19.
J Mater Chem B ; 7(45): 7176-7183, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31651926

RESUMO

Recently, a variety of nanoparticles have been widely used as imaging agents or carriers for the diagnosis and therapy of lung cancer. However, their poor imaging effect, high toxicity, pro-inflammatory effect and ineffective treatment are still a great challenge. In this work, we reported a novel kind of BiOI@CuS nanoparticle to achieve safe and effective therapy of lung cancer by co-loading hydrochloric acid doxorubicin (DOX) and aspirin phenacetin and caffeine (APC). The nanoparticles can effectively relieve inflammatory reactions induced by photo-thermal therapy (PTT). In vitro and in vivo assays showed that DOX/APC co-loaded BiOI@CuS exhibited an effective chemo-photothermal comprehensive therapy effect and good CT imaging capability. Consequently, this multifunctional nanosystem provides a versatile and promising platform in the imaging and treatment of lung cancer in further applications.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Fotoquimioterapia , Tomografia Computadorizada por Raios X , Células A549 , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Aspirina/química , Aspirina/farmacologia , Bismuto/química , Cafeína/química , Cafeína/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Tamanho da Partícula , Fenacetina/química , Fenacetina/farmacologia , Propriedades de Superfície , Células Tumorais Cultivadas
20.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações Medicamentosas , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
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