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Journal of Advanced Research Jul 2022Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered...
INTRODUCTION
Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.
OBJECTIVES
In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.
METHODS
The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.
RESULTS
The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.
CONCLUSION
Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.
Topics: Animals; Chlorzoxazone; Gastrointestinal Microbiome; Metoprolol; Mice; Midazolam; Non-alcoholic Fatty Liver Disease; Omeprazole; Pharmaceutical Preparations; Phenacetin; Tolbutamide
PubMed: 35777915
DOI: 10.1016/j.jare.2021.10.004 -
Clinical Toxicology (Philadelphia, Pa.) Sep 2022Novel opioids in the illicit drug supply, such as the "nitazene" group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory...
BACKGROUND
Novel opioids in the illicit drug supply, such as the "nitazene" group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory depressant effects. We describe three patients in whom -piperidinyl etonitazene, a compound not previously reported in human exposure, was detected after suspected opioid overdose. Other substances that these patients tested for included fentanyl, cocaine, levamisole, phenacetin, benzoylecgonine, -fluorofentanyl, presumptive heroin (tested as 6-monoacetylmorphine (6-MAM), morphine, and codeine), and tramadol.
METHODS
This is a case series of patients with acute opioid overdose enrolled in an ongoing multicenter prospective cohort study. Data collected included reported substance use, clinical course, naloxone dose and response, outcome, and analytes detected in biological samples.
RESULTS
Between October 6, 2020 and October 31, 2021, 1006 patients were screened and 412 met inclusion criteria. Of these, three patients (age 33-55) tested positive for -piperidinyl etonitazene at one site in New Jersey over a period of three days in July 2021. Two patients reported the use of cocaine; one reported the use of heroin and alprazolam. All three patients received naloxone with improvement in their mental status (2 milligrams (mg) intranasally (IN); 8 mg IN; 0.08 mg intravenous (IV)). Two of three received subsequent doses for recurrence of opioid toxicity (0.4-0.6 mg IV). One patient was diagnosed with pneumonia and admitted to the intensive care unit, one was discharged from the Emergency Department (ED), and one used additional drug while in the ED and required admission for a naloxone infusion. None developed organ damage or sequelae.
CONCLUSION
These cases represent a local outbreak of a novel "nitazene" opioid. Public health toxicosurveillance should incorporate routine testing of this emerging class of synthetic compounds in the illicit drug supply.
Topics: Adult; Alprazolam; Analgesics, Opioid; Benzimidazoles; Cocaine; Codeine; Drug Overdose; Fentanyl; Heroin; Humans; Illicit Drugs; Levamisole; Middle Aged; Naloxone; Narcotic Antagonists; Opiate Overdose; Phenacetin; Prospective Studies; Tramadol
PubMed: 35708103
DOI: 10.1080/15563650.2022.2084406 -
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 -
International Journal of Toxicology Aug 2022DNA damage is an established initiating event in the mutagenicity and carcinogenicity of genotoxic chemicals. Accordingly, assessment of this endpoint is critical for...
DNA damage is an established initiating event in the mutagenicity and carcinogenicity of genotoxic chemicals. Accordingly, assessment of this endpoint is critical for chemicals which are being developed for use in humans. To assess the ability of the Chicken Egg Genotoxicity Assay (CEGA) to detect genotoxic pharmaceuticals, a set of 23 compounds with different pharmacological and reported genotoxic effects was tested for the potential to produce nuclear DNA adducts and strand breaks in the embryo-fetal livers using the P-nucleotide postlabeling (NPL) and comet assays, respectively. Due to high toxicity, two aneugens, colchicine and vinblastine, and an autophagy inhibitor, hydroxychloroquine, could not be evaluated. Out of the 20 remaining pharmaceuticals, 10 including estrogen modulators, diethylstilbestrol and tamoxifen, antineoplastics cyclophosphamide, etoposide, and mitomycin C, antifungal griseofulvin, local anesthetics lidocaine and prilocaine, and antihistamines diphenhydramine and doxylamine, yielded clear positive outcomes in at least one of the assays. The antihypertensive vasodilator hydralazine and antineoplastics streptozotocin and teniposide, produced only DNA strand breaks, which were not dose-dependent, and thus, the results with these 3 pharmaceuticals were considered equivocal. No DNA damage was detected for 7 compounds, including the purine antagonist 6-thioguanine, antipyretic analgesics acetaminophen and phenacetin, antibiotic ciprofloxacin, antilipidemic clofibrate, anti-inflammatory ibuprofen, and sedative phenobarbital. However, low solubility of these compounds limited dosages tested in CEGA. Overall, results in CEGA were largely in concordance with the outcomes in other systems in vitro and in vivo, indicating that CEGA provides reliable detection of DNA damaging activity of genotoxic compounds. Further evaluations with a broader set of compounds would support this conclusion.
Topics: Animals; Chickens; Comet Assay; DNA Adducts; DNA Damage; Humans; Mutagenicity Tests; Mutagens; Pharmaceutical Preparations
PubMed: 35658642
DOI: 10.1177/10915818221093583 -
Frontiers in Pharmacology 2022Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive,...
Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive, and time-consuming procedures, pharmacokinetic profiling is still irreplaceable in preclinical studies. With physiologically based pharmacokinetic (PBPK) modeling, the profiles of drug absorption, distribution, metabolism, and excretion can be predicted. To evaluate the application of such an approach in preclinical investigations, the plasma pharmacokinetic profiles of seven commonly used probe substrates of microsomal enzymes, including phenacetin, tolbutamide, omeprazole, metoprolol, chlorzoxazone, nifedipine, and baicalein, were predicted in rats using bottom-up PBPK models built with data alone. The prediction's reliability was assessed by comparison with pharmacokinetic data reported in the literature. The overall predicted accuracy of PBPK models was good with most fold errors within 2, and the coefficient of determination (R) between the predicted concentration data and the observed ones was more than 0.8. Moreover, most of the observation dots were within the prediction span of the sensitivity analysis. We conclude that PBPK modeling with acceptable accuracy may be incorporated into preclinical studies to refine investigations, and PBPK modeling is a feasible strategy to practice the principles of 3Rs.
PubMed: 35645843
DOI: 10.3389/fphar.2022.895556 -
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 -
The Journal of Toxicological Sciences 2022According 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...
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.
Topics: Animals; Blood Specimen Collection; Body Weight; Jugular Veins; Phenacetin; Rats; Rats, Sprague-Dawley; Spleen
PubMed: 35527007
DOI: 10.2131/jts.47.193 -
RSC Advances Oct 2021In this study, molybdenum disulfide (MoS) was chosen as a co-catalyst to enhance the removal efficiency of phenacetin (PNT) in water by a ferrous ion-activated...
In this study, molybdenum disulfide (MoS) was chosen as a co-catalyst to enhance the removal efficiency of phenacetin (PNT) in water by a ferrous ion-activated peroxymonosulfate (Fe/PMS) process. Operating parameters, such as the initial solution pH and chemical dose on PNT degradation efficiency were investigated and optimized. Under an initial pH of 3, an Fe dose of 25 μM, a PMS dose of 125 μM and a MoS dose of 0.1 g L, the degradation efficiency of PNT reached 94.3%, within 15 min. The presence of common water constituents including Cl, HCO , SO and natural organic matter (NOM) will inhibit degradation of PNT in the MoS/Fe/PMS system. Radical quenching tests combined with electron paramagnetic resonance (EPR) results indicated that in addition to free radical species (˙OH, SO˙ and O˙), nonradical reactive species (O) were also crucial for PNT degradation. The variations in the composition and crystalline structure of the MoS before and after the reaction were characterized by XPS and XRD. Further, the degradation pathways of PNT were proposed according to the combined results of LC/TOF/MS and DFT calculations, and primarily included hydroxylation of the aromatic ring, cleavage of the C-N bond of the acetyl-amino group, and cleavage of the C-O bond of the ethoxy group. Finally, toxicity assessment of PNT and its products was predicted using the ECOSAR program.
PubMed: 35493592
DOI: 10.1039/d1ra05892d -
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 -
Pharmaceutics Feb 2022CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of...
CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A2*1F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A2*1F, CYP1A2*1L, CYP1A2*1M, CYP1A2*1V, CYP1A2*1W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype−phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.
PubMed: 35335907
DOI: 10.3390/pharmaceutics14030532