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Pharmaceutical Biology Dec 2018Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics.
CONTEXT
Psoralen and anastrozole are always used together for breast cancer patients in Chinese clinics.
OBJECTIVE
This study investigates the effects of psoralen on the pharmacokinetics of anastrozole in rats and its potential mechanism.
MATERIALS AND METHODS
The pharmacokinetics of orally administered anastrozole (0.5 mg/kg) with (test group) or without (Control group) psoralen pretreatment (20 mg/kg/day for 10 days) in male Sprague-Dawley rats (six rats in each group) were investigated. The plasma concentration of anastrozole was determined using a sensitive and reliable LC-MS/MS method. Additionally, the effects of psoralen on the intestine transport and metabolic stability of anastrozole (1 μM) were investigated using a Caco-2 cell transwell model and rat liver microsome incubation systems.
RESULTS
The results indicated that psoralen could significantly increase the C (from 56.74 ± 3.17 ng/mL to 83.26 ± 6.87 ng/mL), and t (from 10.80 ± 1.05 to 14.29 ± 1.38 h) of anastrozole (p < 0.05). Psoralen could also significantly decrease the efflux ratio of anastrozole from 1.88 to 1.32 (p < 0.05). Additionally, the intrinsic clearance rates of anastrozole decreased significantly (from 62.83 to 43.97 μL/min/mg protein) (p < 0.05) with psoralen pretreatment in rat liver microsome incubation systems.
DISCUSSION AND CONCLUSIONS
This study indicates that when the rats were pretreated with psoralen, the system exposure of anastrozole would be increased significantly. The results showed that the herb-drug interaction between psoralen and anastrozole might occur when they were co-administered, and future studies in humans also need to investigate its herb-drug interaction potential.
Topics: Anastrozole; Animals; Caco-2 Cells; Chromatography, Liquid; Drug Interactions; Ficusin; Humans; Male; Mass Spectrometry; Metabolic Clearance Rate; Microsomes, Liver; Rats; Rats, Sprague-Dawley
PubMed: 30345900
DOI: 10.1080/13880209.2018.1501584 -
ACS Chemical Biology Dec 2019The emergence and spread of antimicrobial resistance is a major public health threat, and there is an urgent need to develop new strategies to address the issue. In this...
The emergence and spread of antimicrobial resistance is a major public health threat, and there is an urgent need to develop new strategies to address the issue. In this study, the possibility of enhancing a whole cell based antibacterial library screen by increasing the dimensionality of the screening effort is explored using methicillin-resistant (MRSA) as the target organism. One dimension involved generating and screening a human liver microsome metabolized FDA approved drug library. Comparative screening of the un-metabolized (UM) and pre-metabolized (PM) libraries allows identification of intrinsically active agents from the UM library screen and of agents with active metabolites from the PM library screen. To further enhance this screening effort, it was combined with a -/+ resistant to antibiotic screen (-/+ cefoxitin; Cef). This allows the identification of agents that can act synergistically with the resistant to antibiotic. This approach revealed five compounds with substantially improved activity after metabolism and four compounds with substantial synergistic activity with cefoxitin. Capecitabine in particular only had significant antibacterial activity after metabolism. Its metabolites were isolated, identified, and characterized for spectrum of activity along with several other anticancer drugs with anti-MRSA activity. Floxuridine, gemcitabine, novobiocin, and rifaximin were identified as having substantial synergy with cefoxitin from the -/+Cef screens. Checkerboard assays verified synergy for these agents. Floxuridine demonstrated a particularly high degree of synergy with cefoxitin (FIC = 0.14). This study demonstrates how a dimensionally enhanced comparative screening effort can identify new antibacterial agents and strategies for countering antibacterial agent resistance.
Topics: Anti-Bacterial Agents; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microsomes, Liver
PubMed: 31675203
DOI: 10.1021/acschembio.9b00745 -
Environment International Apr 2023Increasing evidence indicated that liquid crystal monomers (LCMs) in liquid crystal displays can be released into the environment, and ubiquitously detected in...
Increasing evidence indicated that liquid crystal monomers (LCMs) in liquid crystal displays can be released into the environment, and ubiquitously detected in environmental matrices and even human bodies. Yet databases regarding its uptake and distribution in mammals are lacking. In this study, four LCMs (namely 3dFB, 2OdF3B, 2teFT, and 6OCB) with various physiochemical properties and structures were selected as the target compounds. The LCMs were in vivo and in vitro exposed to mice and rat liver microsomes (RLM). LCMs were found in all mouse tissues, including brain. Pharmacokinetics parameters, C/C, ranged from 27.5 to 214, indicating the preferential deposition of LCMs to tissues rather than blood. The LCMs distributed preferentially to lipophilic tissues, and relative mass contribution of LCMs from liver and adipose was 43-98 %. The physicochemical properties (i.e., Kow, molecular weight, and functional groups) had pronounced effect on distribution and accumulation of LCMs. The 2teFT with the highest Kow and molecular weight showed the relatively higher accumulation potential and half elimination time in all the tissues. The 6OCB containing cyano-group was more accumulative than the fluorinated 3dFB with the comparable Kow. In RLM assays, 2teFT and 6OCB were resistant to metabolic degradation. While 3dFB and 2OdF3B underwent rapid degradation with 93.7 % and 72.4 % being metabolized at 360 min. Findings in this study bear significant implications for the biomonitoring and overall risk evaluation of LCMs.
Topics: Mice; Rats; Humans; Animals; Liquid Crystals; Brain; Microsomes, Liver; Liver; Mammals
PubMed: 37003217
DOI: 10.1016/j.envint.2023.107894 -
Journal of Medicinal Chemistry Jul 2021The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and...
The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable -acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors and have a BRD4 D1 of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-α-stimulated A549 cells. These data indicate that and are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.
Topics: A549 Cells; Cell Cycle Proteins; Cell Survival; Dose-Response Relationship, Drug; Humans; Lysine; Microsomes, Liver; Molecular Structure; Structure-Activity Relationship; Transcription Factors; Triazoles
PubMed: 34236185
DOI: 10.1021/acs.jmedchem.1c00933 -
Journal of Enzyme Inhibition and... Dec 2022Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability.... (Comparative Study)
Comparative Study
Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability.
Topics: Animals; Carboxylesterase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Esters; Hydrolysis; Male; Microsomes, Liver; Models, Molecular; Molecular Structure; Prodrugs; Rats; Rats, Wistar; Structure-Activity Relationship
PubMed: 35156494
DOI: 10.1080/14756366.2022.2027933 -
Xenobiotica; the Fate of Foreign... Sep 2021Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD and...
Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD and .Mouse and human liver microsomes were employed to identify POD metabolites and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
Topics: Animals; Antiviral Agents; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Mice; Microsomes, Liver; Podophyllotoxin; Tandem Mass Spectrometry
PubMed: 34319859
DOI: 10.1080/00498254.2021.1961920 -
Comparative Pharmacokinetics of Δ-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats.Cannabis and Cannabinoid Research Dec 2022Studies in rodent models have shown that adolescent exposure to Δ-THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function...
Studies in rodent models have shown that adolescent exposure to Δ-THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function and behavior. However, our understanding of how age and sex might influence the distribution and metabolism of THC in laboratory rodents is still incomplete. In the present report, we provide a comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes, and outline several dissimilarities across these groups. A single (acute) or 2-week daily (subchronic) administration of THC (0.5 or 5 mg/kg, acute; 5 mg/kg, subchronic; intraperitoneal) was given to adolescent (33-day-old, acute; 30-44-day-old, subchronic) and young adult (70-day-old, acute only) male and female rats. THC and its first-pass metabolites-11-hydroxy-Δ-THC (11-OH-THC) and 11-nor-9-carboxy-Δ-THC (11-COOH-THC)-were quantified in plasma and brain tissue using a selective isotope-dilution liquid chromatography/tandem mass spectrometry assay. Changes in body temperature were measured using abdominally implanted microchips. Biotransformation of THC to its metabolites using freshly prepared liver microsomes was assessed. At the acute 5 mg/kg dose, maximal plasma concentrations of THC were twice as high in adult than in adolescent rats. Conversely, in adults, brain concentrations and brain-to-plasma ratios for THC were substantially lower (25-50%) than those measured in adolescents. Similarly, plasma and brain concentrations of THC metabolites were higher in adolescent male rats compared with adult males. Interestingly, plasma and brain concentrations of the psychoactive THC metabolite 11-OH-THC were twofold to sevenfold higher in female animals of both ages compared with males. Moreover, liver microsomes from adolescent males and adolescent and adult females converted THC to 11-OH-THC twice as fast as adult male microsomes. A dose-dependent hypothermic response to THC was observed in females with 0.5 and 5 mg/kg THC, whereas only the highest dose elicited a response in males. Finally, subchronic administration of THC during adolescence did not significantly affect the drug's PK profile. The results reveal the existence of multiple age and sex differences in the distribution and metabolism of THC in rats, which might influence the pharmacological response to the drug.
Topics: Female; Male; Animals; Rats; Dronabinol; Microsomes
PubMed: 35353551
DOI: 10.1089/can.2021.0205 -
Future Medicinal Chemistry Mar 2022
Topics: Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Microsomes; Prostaglandin-E Synthases
PubMed: 34985304
DOI: 10.4155/fmc-2021-0317 -
Bioorganic & Medicinal Chemistry Feb 2017TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target...
TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.
Topics: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; MAP Kinase Kinase Kinases; Mice; Microsomes, Liver; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship
PubMed: 28011204
DOI: 10.1016/j.bmc.2016.11.035 -
Molecules (Basel, Switzerland) Jun 2023Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the...
Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC 6.8) against . Furthermore, we identified several other BIPPO analogs (, , and ) with potent antimalarial activity (pIC > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.
Topics: Mice; Animals; Antimalarials; Malaria; Plasmodium falciparum; Microsomes, Liver; Drug Resistance; Folic Acid Antagonists
PubMed: 37446602
DOI: 10.3390/molecules28134939