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Molecules (Basel, Switzerland) Oct 2023In this work, we present a comprehensive study of the thermodynamic properties of 3-and 4-ethoxyacetanilides. The heat capacities in crystalline, liquid, and supercooled...
In this work, we present a comprehensive study of the thermodynamic properties of 3-and 4-ethoxyacetanilides. The heat capacities in crystalline, liquid, and supercooled liquid states from 80 to 475 K were obtained using adiabatic, differential scanning (DSC), and fast scanning (FSC) calorimetries. The fusion enthalpies at were combined from DSC measurement results and the literature data. The fusion enthalpies at 298.15 K were evaluated in two independent ways: adjusted according to Kirchhoff's law of thermochemistry, and using Hess' law. For the latter approach, the enthalpies of the solution in DMF in crystalline and supercooled liquid states were derived. The values obtained by the two methods are consistent with each other. The standard thermodynamic functions (entropy, enthalpy, and Gibbs energy) between 80 and 470 K were calculated.
PubMed: 37894506
DOI: 10.3390/molecules28207027 -
Microorganisms Jul 2023Phenacetin, an antipyretic and analgesic drug, poses a serious health risk to both humans and aquatic organisms, which is of concern since this micropollutant is...
Phenacetin, an antipyretic and analgesic drug, poses a serious health risk to both humans and aquatic organisms, which is of concern since this micropollutant is frequently detected in various aquatic environments. However, rare pure bacterial cultures have been reported to degrade phenacetin. Therefore, in this study, the novel phenacetin-degrading strain PNT-23 was isolated from municipal wastewater and identified as a sp. based on its morphology and 16S rRNA gene sequencing. The isolated strain could completely degrade 100 mg/L phenacetin at an inoculum concentration of OD 1.5 within 80 h, utilizing the micropollutant as its sole carbon source for growth. Strain PNT-23 exhibited optimal growth in LB medium at 37 °C and a pH of 7.0 with 1% NaCl, while the optimal degradation conditions in minimal medium were 30 °C and a pH of 7.0 with 1% NaCl. Two key intermediates were identified during phenacetin biodegradation by the strain PNT-23: N-acetyl-4-aminophenol and 4-aminophenol. This study provides novel insights into the biodegradation of phenacetin using a pure bacterium culture, expands the known substrate spectra of strains and presents a potential new candidate for the microbial removal of phenacetin in a diverse range of environments.
PubMed: 37630522
DOI: 10.3390/microorganisms11081962 -
Drug Metabolism and Bioanalysis Letters 2023Saccharolactone is used as a β-glucuronidase inhibitor in in vitro microsomal and recombinant uridine diphosphoglucuronosyl transferases (rUGTs) incubations to enhance...
BACKGROUND
Saccharolactone is used as a β-glucuronidase inhibitor in in vitro microsomal and recombinant uridine diphosphoglucuronosyl transferases (rUGTs) incubations to enhance glucuronide pathway and, thereby, formation of glucuronide metabolites. We investigated its effect on CYP mediated metabolism of drugs (compound-174, phenacetin and quinidine) using human liver microsomes (HLM) supplemented with Phase-1 and Phase-2 co-factors.
METHODS
Compounds were incubated in HLM supplemented with co-factors to assess Phase-1 (NADPH) and Phase-2 (NADPH, alamethicin, saccharolactone and UDPGA) metabolism. CYP phenotype assay for compound-174 was conducted in HLM (± 1-ABT) and human recombinant CYP isoforms. CYP inhibition profile of saccharolactone was also generated in HLM.
RESULTS
The metabolism of compound-174, phenacetin and quinidine in HLM significantly decreased in reactions containing additional components like alamethicin, saccharolactone and UDPGA and indicated that the addition of saccharolactone inhibited the metabolism. Phenacetin and quinidine are known substrates of CYP1A2 and CYP3A4 isoforms. The metabolism of compound- 174 was significantly inhibited in the presence of 1-ABT in HLM, and CYP3A4 and CYP2C8 isoforms were found to be the predominant isoforms responsible for its metabolism. Further evaluation of CYP inhibition in HLM indicated saccharolactone to be a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms with IC values of less than 4 mM.
CONCLUSION
The findings indicated that saccharolactone being a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms (IC < 4 mM), resulted in significant inhibition of the metabolism of compound-174, phenacetin and quinidine in HLM and caution should be exercised in using it with proper titration of the concentrations.
Topics: Humans; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Cytochrome P-450 CYP3A; Glucuronides; Uridine Diphosphate Glucuronic Acid; Quinidine; Xenobiotics; NADP; Phenacetin; Microsomes, Liver; Protein Isoforms; Peptaibols
PubMed: 37612873
DOI: 10.2174/2949681016666230823094423 -
Biopharmaceutics & Drug Disposition Oct 2023Suberosin is a natural phytoconstituent isolated from Citropsis articulata, especially employed for its anticoagulant properties. Although metabolic studies assessing...
Suberosin is a natural phytoconstituent isolated from Citropsis articulata, especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0-50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin O-deethylation, exhibiting IC values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb-drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.
Topics: Humans; Cytochrome P-450 CYP1A2; Microsomes, Liver; Cytochrome P-450 Enzyme Inhibitors; Phenacetin; Cytochrome P-450 Enzyme System
PubMed: 37448189
DOI: 10.1002/bdd.2370 -
Archives of Razi Institute Feb 2023Acetaminophen is a pharmaceutical synthesized non-opioid analgesic that belongs to the "aniline analgesics" class of medicine. Because it lacks a significant...
Acetaminophen is a pharmaceutical synthesized non-opioid analgesic that belongs to the "aniline analgesics" class of medicine. Because it lacks a significant anti-inflammatory effect, it is not classified as a non-steroidal anti-inflammatory therapeutic medication (NSAID). As an over-the-counter pain reliever and antipyretic, Acetaminophen is the active metabolite of phenacetin and acetanilide, but it is less toxic than either precursor. According to some medical studies, Acetaminophen toxicity can be treated with vitamin B12. Acetaminophen-poisoned Male Wister rats were the subject model of the current study, which examines the effects of vitamin B12 on their hepatic health. There were three groups of animals: Acetaminophen treated animals (750 ml/kg), vitamin B12-treated animals (0.63 g/kg), and a control group that received distilled water (750 ml/kg). All animals were given oral medication for seven days. On the seventh day, the animal was sacrificed. Plasma levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Glutathione (GSH), total antioxidant capacity (TAC), Caspase3, Malondialdehyde (MDA), Interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-) were measured in the cardiac blood samples. Vitamin B12 lowers liver enzyme levels in the blood, increases overall antioxidant levels, and compensates for tissue glutathione deficiency while lowering serum elevations. TNF-α and interleukin-6 levels are also reduced by caspase3. Acetaminophen-induced hepatic necrosis and inflammatory cell infiltration were both considerably reduced by vitamin B12 supplementation. According to this study, vitamin B12 was found to have a protective effect against acetaminophen-induced hepatotoxicity.
Topics: Male; Animals; Rats; Rats, Wistar; Acetaminophen; Vitamin B 12; Antioxidants; Interleukin-6; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury
PubMed: 37312722
DOI: 10.22092/ARI.2022.359353.2408 -
PloS One 2023GL-V9, a new synthetic flavonoid derived from wogonin, has shown beneficial biological functions. In this study, accurate and sensitive UPLC-MS/MS methods were developed...
GL-V9, a new synthetic flavonoid derived from wogonin, has shown beneficial biological functions. In this study, accurate and sensitive UPLC-MS/MS methods were developed and validated for the quantification of GL-V9 and its glucuronide metabolite (5-O-glucuronide GL-V9) in Beagle dog plasma. The chromatographic separation was performed on a C8 column (ACE Excel 5 C8 50×3.0 mm) using 0.1% formic acid and acetonitrile were used as mobile phase. Mass detection was performed on a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) interface operating in positive ion mode. Quantitative analysis was performed in multiple reaction monitoring (MRM) mode with the transitions of m/z 410.2→126.1 for GL-V9, m/z 586.3→410.0 for 5-O-glucuronide GL-V9 and m/z 180.0→110.3 for phenacetin (internal standard), respectively. The calibration curves for GL-V9 and 5-O-glucuronide GL-V9 showed excellent linearity over the concentration range of 0.5-500 ng/mL with correlation coefficient greater than 0.99. The intra- and inter-day accuracies were within 99.86% to 109.20% for GL-V9 and 92.55% to 106.20% for 5-O-glucuronide GL-V9, respectively. The mean recovery was 88.64% ± 2.70% for GL-V9, and 92.31% ± 6.28% for 5-O-glucuronide GL-V9, respectively. The validated method was successfully applied to the pharmacokinetic study in Beagle dogs after oral and intravenous administration. The oral bioavailability of GL-V9 was approximately 2.47%~4.35% in Beagle dogs and reached steady state on the fifth day after repeated dosing.
Topics: Dogs; Animals; Tandem Mass Spectrometry; Chromatography, Liquid; Chromatography, High Pressure Liquid; Glucuronides; Flavonoids; Reproducibility of Results
PubMed: 37285365
DOI: 10.1371/journal.pone.0286467 -
The Science of the Total Environment Aug 2023An untargeted study of multiclass contaminants associated with microplastics (MPs) in the East Mediterranean was carried out. Samples were collected in 2020-2021 from...
An untargeted study of multiclass contaminants associated with microplastics (MPs) in the East Mediterranean was carried out. Samples were collected in 2020-2021 from the shoreline at 14 different locations, along the Lebanese coast. Attenuated Total Reflectance (ATR) FTIR spectroscopy showed the predominant presence of polyethylene and polypropylene among plastic debris. The non-polar and polar organic compounds sorbed on the MPs were identified and quantified by GC - TOF MS and LC - electrospray MS/MS, respectively. Deconvolution of accurate GC-MS scan data allowed the identification of >130 organic pollutants, 64 of which could be confirmed by matching with the authentic standards, among which a number of previously unreported in targeted GC-MS(MS) methods. In addition to highly toxic, legacy chlorinated pollutants, high levels (average values from 0.8 to 4.0 μg g) of some musks, UV filters and UV absorbers were detected. Untargeted LC-MS demonstrated the persistence of several pesticides (i.e., chlorpyrifos) and pharmaceuticals, such as phenacetin and minoxidil, which were quantified. In addition, a study of metals associated with microplastics using ICP-MS confirmed the high potential of microplastics to act as a vector of, among others, toxic metals, such as Cd, Pb, Bi or Hg.
Topics: Gas Chromatography-Mass Spectrometry; Microplastics; Plastics; Chromatography, Liquid; Tandem Mass Spectrometry; Metals; Spectrum Analysis; Environmental Pollutants; Water Pollutants, Chemical
PubMed: 37172849
DOI: 10.1016/j.scitotenv.2023.164111 -
IUCrData Apr 2023The title compound, CHNO, crystallizes with a disordered nitro group in twinned crystals. Both the meth-oxy group and the acetamide groups are nearly coplanar with the...
The title compound, CHNO, crystallizes with a disordered nitro group in twinned crystals. Both the meth-oxy group and the acetamide groups are nearly coplanar with the phenyl ring, and the C-N-C-O torsion angle [0.2 (4)°] is also insignificantly different from zero. Overall, the 12-atom meth-oxy-phenyl-acetamide group is nearly planar, with an r.m.s. deviation of 0.042 Å. The nitro group is twisted out of this plane by about 30°, disordered into two orientations with opposite senses of twist. In the crystal, the N-H group donates a hydrogen bond to a nitro oxygen atom, generating chains propagating in the [101] direction. The amide carbonyl oxygen atom is not involved in the hydrogen bonding.
PubMed: 37151207
DOI: 10.1107/S2414314623002985 -
European Journal of Clinical... Jun 2023Pregnancy-mediated physiological and biochemical changes contribute to alterations in the pharmacokinetics of certain drugs. There is a paucity of data on the systematic...
A cocktail probe approach to evaluate the effect of hormones on the expression and activity of CYP enzymes in human hepatocytes with conditions simulating late stage of pregnancy.
PURPOSE
Pregnancy-mediated physiological and biochemical changes contribute to alterations in the pharmacokinetics of certain drugs. There is a paucity of data on the systematic evaluation of the underlying mechanisms. The objective of the current study was to examine the impact of changes in circulating and tissue hormonal concentration during the late stage of pregnancy on the activity and expression of hepatic cytochrome P450 (CYP) enzymes using a cocktail probe approach.
METHODS
Freshly isolated primary human hepatocytes were incubated with third trimester physiologic (plasma) and projected liver (ten-fold higher) concentrations of female hormones: progesterone (2 µM), estradiol (0.3 µM), estriol (0.8 µM), estrone (0.2 µM), 17α-hydroxyprogesterone (0.1 µM), and human growth hormone (0.005 µM). The metabolic activity of the hepatocytes was assessed using a cocktail of isozyme-specific P450 probe substrates (CYP1A2 (phenacetin), CYP2C9 (diclofenac), CYP2C19 (S-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (testosterone)). A validated LC-MS/MS assay was used to measure the corresponding metabolite concentrations. CYP450 protein and mRNA levels were measured using western blot and qRT-PCR, respectively.
RESULTS
Female hormones at projected third-semester hepatic concentrations significantly enhanced mRNA and protein expression and increased the metabolic activity of CYP3A4. The expression and activity of other CYP450 enzymes studied were not affected by mixtures of female hormones at concentrations used.
CONCLUSION
The increased activity of CYP3A4 is consistent with the clinically observed increase in clearance of CYP3A4 substrates during pregnancy. Overall expression and activity of CYP450 isozymes are differentially regulated during pregnancy.
Topics: Humans; Female; Pregnancy; Cytochrome P-450 CYP3A; Chromatography, Liquid; Tandem Mass Spectrometry; Cytochrome P-450 Enzyme System; Hepatocytes; Hormones; Microsomes, Liver
PubMed: 37060457
DOI: 10.1007/s00228-023-03489-1