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Food and Chemical Toxicology : An... Jul 2022Herbal tea is a highly popular and widely consumed beverage. However, a pain-relieving and fever-reducing drug, acetophenetidin, was recently found to illegally occur in...
Herbal tea is a highly popular and widely consumed beverage. However, a pain-relieving and fever-reducing drug, acetophenetidin, was recently found to illegally occur in herbal tea for a fraud purpose. Due to the potential health risk and urgent requirement for on-site screening method, a one-step and high specificity strip for identifying acetophenetidin was developed for the first time. Assisted by computational chemistry, four haptens were designed to prepare immunogens and coating antigens for antibody generation, and a specific antibody with ultra-sensitivity and high specificity was generated, showing half maximal inhibitory (IC) of 16.46 ng/mL for acetophenetidin, less than 3.5% of cross-reactivity to analogs by ELISA. A gold nanoparticles immunochromatographic strip was developed for detection of acetophenetidin in herbal tea, demonstrating a cut-off value of 160 ng/mL and a limit of detection of 1.63 ng/mL. The recovery rates were ranged from 102.2% to 106.1% with coefficient of variation between 2.21% and 7.20%. The analysis of real samples (n = 20) by the strip was well correlated with that of the confirmatory method, liquid chromatography-tandem mass spectrometry. The proposed strip has the potential to be used for rapid screening of acetophenetidin in herbal tea.
Topics: Antibodies; Fraud; Gold; Limit of Detection; Metal Nanoparticles; Phenacetin; Teas, Herbal
PubMed: 35643229
DOI: 10.1016/j.fct.2022.113183 -
Chemical Research in Toxicology May 2022Sunitinib is an orally administered tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity; however, the mechanisms of this toxicity remain unclear. We...
Sunitinib is an orally administered tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity; however, the mechanisms of this toxicity remain unclear. We have previously shown that cytochromes P450 1A2 and 3A4 catalyze sunitinib metabolic activation via oxidative defluorination leading to a chemically reactive, potentially toxic quinoneimine, trapped as a glutathione (GSH) conjugate (M5). The goals of this study were to determine the impact of interindividual variability in P450 1A and 3A activity on sunitinib bioactivation to the reactive quinoneimine and sunitinib -dealkylation to the primary active metabolite -desethylsunitinib (M1). Experiments were conducted using single-donor human liver microsomes and human hepatocytes. Relative sunitinib metabolite levels were measured by liquid chromatography-tandem mass spectrometry. In human liver microsomes, the P450 3A inhibitor ketoconazole significantly reduced M1 formation compared to the control. The P450 1A2 inhibitor furafylline significantly reduced defluorosunitinib (M3) and M5 formation compared to the control but had minimal effect on M1. In -genotyped human liver microsomes from 12 individual donors, M1 formation was highly correlated with P450 3A activity measured by midazolam 1'-hydroxylation, and M3 and M5 formation was correlated with P450 1A2 activity estimated by phenacetin -deethylation. M3 and M5 formation was also associated with P450 3A5-selective activity. In sandwich-cultured human hepatocytes, the P450 3A inducer rifampicin significantly increased M1 levels. P450 1A induction by omeprazole markedly increased M3 formation and the generation of a quinoneimine-cysteine conjugate (M6) identified as a downstream metabolite of M5. The nonselective P450 inhibitor 1-aminobenzotriazole reduced each of these metabolites (M1, M3, and M6). Collectively, these findings indicate that P450 3A activity is a key determinant of sunitinib -dealkylation to the active metabolite M1, and P450 1A (and potentially 3A5) activity influences sunitinib bioactivation to the reactive quinoneimine metabolite. Accordingly, modulation of P450 activity due to genetic and/or nongenetic factors may impact the risk of sunitinib-associated toxicities.
Topics: Activation, Metabolic; Chromatography, Liquid; Cytochrome P-450 CYP3A; Glutathione; Humans; Microsomes, Liver; Sunitinib
PubMed: 35484684
DOI: 10.1021/acs.chemrestox.1c00426 -
Frontiers in Pharmacology 2020Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib...
Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The experiment was carried out by using rat liver microsomes (RLMs), whereas the experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration ( < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.
PubMed: 33746741
DOI: 10.3389/fphar.2020.593518 -
The International Journal on Drug Policy Jul 2020Since it's first implementatation in 1984, Syringe Exchange Programs (SEP) are a critical component of harm reduction interventions among people who inject drugs.. The...
BACKGROUND
Since it's first implementatation in 1984, Syringe Exchange Programs (SEP) are a critical component of harm reduction interventions among people who inject drugs.. The aim of this work was to use a scientific analytical approach to obtain drug use information through the analysis of the content of used syringes.
METHODS
357 syringes were collected in New York City and submitted to qualitative analysis. Screening analysis was performed by gas chromatography mass spectrometry (GC-MS) and confirmatory analysis by liquid chromatography quadrupole time of flight mass spectrometry (LC-QTOF).
RESULTS
Of the 357 syringes analyzed, 275 (77.0%) were positive for one or more substances. The most common drug of abuse identified was heroin/related substances (72.0%), followed by cocaine/related substance (34.9%), fentanyl/related substance (13.5%), methamphetamine/related substance (7.6%) and furanylfentanyl (3.6%). Quinine/quinidine (18.5%) was the most common cutting agent detected, followed by levamisole (12.0%), caffeine (11.6%), lidocaine (11.6%), and phenacetin (6.9%).
CONCLUSION
Analysis of samples collected from a drug street scenario allows the identification of new substances being injected and provides information to harm reduction programs to identify strategies to reduce drug abuse.
Topics: Harm Reduction; Humans; Illicit Drugs; Needle-Exchange Programs; New York City; Substance Abuse, Intravenous; Syringes
PubMed: 32442881
DOI: 10.1016/j.drugpo.2020.102770 -
Journal of Chromatography. A Jul 2022Plastic antioxidants (PAOs), which are used in the industry to prevent degradation caused by thermo-mechanical or thermo-oxidative conditions, have been found in cocaine...
Plastic antioxidants (PAOs), which are used in the industry to prevent degradation caused by thermo-mechanical or thermo-oxidative conditions, have been found in cocaine products seized by the Civil Police of the Federal District, Brazil, since 2019. In this study, a 4-meter short column gas chromatography-mass spectrometry (GC-MS) qualitative method was optimized and validated to detect cocaine, PAOs (antioxidant 168, FOS; antioxidant 1076, NOX; and butylated hydroxytoluene, BHT) and 16 other cutting agents in cocaine base and salt. NOX and FOS are high-boiling-point compounds that are not amenable to the standard GC-MS methods. The method uses a 250 °C split mode injection, final temperature of 280 °C, and a total run time of 16.5 min. PAOs were found in 84.2% of the 38 cocaine base samples and in 21.5% of the 65 cocaine salt samples (mainly NOX); 20 samples that did not contain any cocaine also contained PAOs (30% NOX and 25% FOS). Other cutting agents found in the samples included phenacetin, aminopyrine, and lidocaine in cocaine base; lidocaine, tetracaine, and caffeine in cocaine salt. This is the first report of PAOs detected as cocaine cutting agents and shows another important application of the short column GC-MS method in forensic science that can also be applied in other areas involving these compounds.
Topics: Antioxidants; Cocaine; Gas Chromatography-Mass Spectrometry; Lidocaine; Plastics
PubMed: 35660316
DOI: 10.1016/j.chroma.2022.463170 -
European Journal of Drug Metabolism and... Dec 2019Honokiol, a major constituent isolated from Magnolia officinalis, is regarded as a phytochemical marker and bioactive substance present in many traditional Chinese...
BACKGROUND AND OBJECTIVES
Honokiol, a major constituent isolated from Magnolia officinalis, is regarded as a phytochemical marker and bioactive substance present in many traditional Chinese medicines. However, the effect of honokiol on cytochrome P450 (CYP) has not been thoroughly investigated. The aim of this study was to investigate the effect of honokiol on CYP1A2 and CYP2C11 in vitro and in vivo.
METHODS
The effect of honokiol on CYP1A2 and CYP2C11 was investigated with rat liver microsomes (RLMs) by measuring phenacetin and tolbutamide metabolism (probe drugs for CYP1A2 and CYP2C11, respectively), and then explored in vivo by measuring the effect of honokiol (2.5 and 5 mg/kg, intravenous injection) on the pharmacokinetics of theophylline and tolbutamide (probe drugs for CYP1A2 and CYP2C11, respectively) in rats in vivo.
RESULTS
Honokiol inhibited the formation of acetaminophen from phenacetin and 4-hydroxytolbutamide from tolbutamide in RLMs, with inhibition constant (K) values of 1.6 μM and 16.5 μM, respectively. In vivo, honokiol (2.5 or 5.0 mg/kg) increased the half-life (t) of theophylline by 40.9% and 119.9%, decreased the clearance (CL) by 23.8% and 42.9%, and increased the area under the curve (AUC) by 41.3% and 83.4%, respectively. Similarly, the t of tolbutamide increased by 25.5% and 33.8%, the CL decreased by 14.3% and 19.1%, and the AUC increased by 19.2% and 25.7%, respectively.
CONCLUSION
The inhibition of CYP1A2 by honokiol is greater than the inhibition of CYP2C11. The changes in the pharmacokinetics of theophylline and tolbutamide in rats treated with honokiol are due to the inhibition of CYP1A2 and CYP2C11 activity in a dose-dependent manner.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Biphenyl Compounds; Cytochrome P-450 CYP1A2; Cytochrome P450 Family 2; Cytochromes; Lignans; Male; Rats; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase; Theophylline; Tolbutamide
PubMed: 31175627
DOI: 10.1007/s13318-019-00565-9 -
MethodsX 2022The data presented in this article are related to the research article entitled "Cytochrome P450 inhibition activities of non-standardized botanical products" [1], in...
The data presented in this article are related to the research article entitled "Cytochrome P450 inhibition activities of non-standardized botanical products" [1], in which the possible CYP inhibitory properties of botanical products were investigated. This article describes the optimization and bioanalytical method validation of the CYP (Cytochrome P450 inhibition assay) inhibition assays, namely, phenacetin O-deethylase assay, testosterone 6β-hydroxylase assay, felodipine dehydrogenase assay and midazolam 1'-hydroxylase assay using LC-MS/MS.
PubMed: 36081487
DOI: 10.1016/j.mex.2022.101827 -
International Journal of Toxicology 2022Drug powder composition analysis is of particular interest in forensic investigations to identify illicit substance content, cutting agents and impurities. Powder...
Drug powder composition analysis is of particular interest in forensic investigations to identify illicit substance content, cutting agents and impurities. Powder profiling is difficult to implement due to multiple analytical methods requirement and remains a challenge for forensic toxicology laboratories. Furthermore, visualization tools allowing seizure products identification appear to be under-used to date. The aim of this study is to present the utility of molecular networking for the composition establishment of natural origin drugs. A powder suspected to contain heroin and three powders suspected to contain cocaine obtained from law enforcement agency seizures were analyzed using untargeted screening by liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS/MS). Molecular networking and metabolite annotation applied to suspected heroin sample allowed rapid confirmation of its illicit content (heroin), the identification of structurally related major impurities (6-monoacetylmorphine, 6-monoacetylcodeine, noscapine, and papaverine), as well as cutting agents (acetaminophen and caffeine). The cocaine powder profiling allowed the comparison of its constituents in a semi-quantitative manner (cocaine, benzoylecgonine, trans/cis-cinnamoylcocaine, trimethoxycocaine, hexanoylecgonine methylester, caffeine, hydroxyzine, levamisole, and phenacetin), bringing additional information for their identification, including geographically sourcing of natural product and their putative place in the supply chain. Although this approach does not replace the profiling techniques used by forensic laboratories, the use of molecular networks provides a visual overview of structurally related constituents which aids the comparison and investigation of seizure powders. Molecular networks offers here an ideal way to depict structurally related and unrelated compounds in these often complex mixtures of chemicals.
Topics: Acetaminophen; Caffeine; Heroin; Humans; Illicit Drugs; Seizures
PubMed: 35212556
DOI: 10.1177/10915818211065161 -
The Science of the Total Environment Jan 2022Phenacetin (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...
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 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.
Topics: Ammonia; Bioreactors; Metagenomics; Nitrification; Nitrites; Nitrogen; Oxidation-Reduction; Phenacetin
PubMed: 34525735
DOI: 10.1016/j.scitotenv.2021.150068 -
Molecules (Basel, Switzerland) Oct 2023Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its...
Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its potential for drug-drug interactions related to cytochrome P450 (CYP450) enzymes, the effect of the inhibitory mechanisms of LKMS on CYP450 enzymes is still unclear. Thus, this study aimed to evaluate the inhibitory effects of LKMS on dog CYP450 enzymes. A cocktail approach using ultra-performance liquid chromatography-tandem mass spectrometry was conducted to investigate the inhibitory effect of LKMS on canine CYP450 enzymes. Typical probe substrates of phenacetin, coumarin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and testosterone were used for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, respectively. This study showed that LKMS might not be a time-dependent inhibitor. LKMS inhibited CYP2A6, CYP2B6, and CYP2D6 via mixed inhibition. LKMS exhibited mixed-type inhibition against the activity of CYP2A6 with an inhibition constant (K) value of 135.6 μΜ. LKMS inhibited CYP2B6 in a mixed way, with K values of 59.44 μM. A phenotyping study based on an inhibition assay indicated that CYP2D6 contributes to the biotransformation of LKMS. A mixed inhibition of CYP2D6 with K values of 64.87 μM was also observed. Given that this study was performed in vitro, further in vivo studies should be conducted to identify the interaction between LKMS and canine CYP450 enzymes to provide data support for the clinical application of LKMS and the avoidance of adverse interactions between other drugs.
Topics: Dogs; Animals; Tandem Mass Spectrometry; Chromatography, Liquid; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Microsomes, Liver; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Liver
PubMed: 37894672
DOI: 10.3390/molecules28207193