Current Drug Metabolism[JOURNAL]
Sun
200 papers
Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.
Zhuo Y, Chen H, Liu C … +8 more , Zhang Y, Fang J, Li M, Wang Z, Jiang Q, Yu L, Pan H, Wang Q
Curr Drug Metab · 2023 · PMID 37519003 · Publisher ↗
BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsat...
BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor. CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).
Worldwide Prevalence of Polypharmacy: A Systematic Review.
Januário BD, Mafra NS, de Souza Silva H … +5 more , Carvalho IM, Sena ALS, Pereira APGS, de Faria Júnior NS, Campos HO
Curr Drug Metab · 2023 · PMID 37497705 · Publisher ↗
INTRODUCTION: The present study has compiled the prevalence of polypharmacy worldwide and assessed the prevalence of polypharmacy in different populations, including community-dwelling individuals, hospitalized patients,...
INTRODUCTION: The present study has compiled the prevalence of polypharmacy worldwide and assessed the prevalence of polypharmacy in different populations, including community-dwelling individuals, hospitalized patients, and institutionalized patients. METHODS: This systematic review was conducted and reported according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A systematic search of electronic databases, including PubMed, Web of Science, and Scielo, was performed in March 2021 without any date and language restrictions. Combinations of the following keywords were used for the search strategy: polypharmacy OR multiple medications OR multiple medicines OR multiple drug AND prevalence. Based on the search and inclusion criteria, two hundred and eight studies (73,076,167 individuals) were selected for inclusion in the systematic review. It was observed that there is a wide variation in the prevalence of polypharmacy between studies. RESULTS: The prevalence of polypharmacy was found to be 30.2%, 61.7%, and 56.9% for community-dwelling individuals, hospitalized patients, and institutionalized patients, respectively. CONCLUSION: Based on the analyses, this systematic review has demonstrated a wide variation in the prevalence of polypharmacy between studies and countries and a high prevalence of polypharmacy in institutionalized and hospitalized patients.
Synthesis and Biomedical Applications of DNA Hydrogel.
Zhang Q, Lin S, Shi J
Curr Drug Metab · 2023 · PMID 37431900 · Publisher ↗
Deoxyribonucleic acid (DNA), as a natural polymer material, carries almost all the genetic information and is recognized as one of the most intelligent natural polymers. In the past 20 years, there have been many excitin...
Deoxyribonucleic acid (DNA), as a natural polymer material, carries almost all the genetic information and is recognized as one of the most intelligent natural polymers. In the past 20 years, there have been many exciting advances in the synthesis of hydrogels using DNA as the main backbone or cross-linking agent. Different methods, such as physical entanglement and chemical cross-linking, have been developed to perform the gelation of DNA hydrogels. The good designability, biocompatibility, designable responsiveness, biodegradability and mechanical strength provided by DNA building blocks facilitate the application of DNA hydrogels in cytoscaffolds, drug delivery systems, immunotherapeutic carriers, biosensors and nanozyme-protected scaffolds. This review provides an overview of the main classification and synthesis methods of DNA hydrogels and highlights the application of DNA hydrogel in biomedical fields. It aims to give readers a better understanding of DNA hydrogels and development trends.
Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [H]Catalpol in Rats: the Main Bioactive Component of for the Treatment of Ischemic Stroke.
Ge X, Zheng Y, He Y … +6 more , Chen C, Yang C, Lu S, Xuan Z, Zhong D, Diao X
Curr Drug Metab · 2023 · PMID 37409552 · Publisher ↗
BACKGROUND: Catalpol, one of the main bioactive components isolated from , was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabo...
BACKGROUND: Catalpol, one of the main bioactive components isolated from , was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate. OBJECTIVE: This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [H]catalpol in rats. METHODS: Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q-Exactive plus MS. RESULTS: The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median of 0.75 h and an arithmetic mean half-life () of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drugrelated substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems. CONCLUSIONS: Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.
Computational Structural Validation of Mutations and Evaluation of Machine Learning Algorithms in Predicting the Therapeutic Outcomes of Warfarin.
Sridharan K, D TK, Manikandan S … +4 more , Prasanna G, Guruswamy L, Al Banna R, Doss C GP
Curr Drug Metab · 2023 · PMID 37409551 · Publisher ↗
AIM: The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools. BACKGROUND: Warfarin, a commonly used anticoa...
AIM: The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools. BACKGROUND: Warfarin, a commonly used anticoagulant drug, is influenced by cytochrome P450 (CYP) enzymes, particularly . MLAs have been identified to have great potential in personalized therapy. OBJECTIVE: The purpose of the study was to evaluate MLAs in predicting the critical outcomes of warfarin therapy and validate the key predictor genotyping variable using bioinformatics tools. METHODS: An observational study was conducted on adults receiving warfarin. Allele discrimination method was used for estimating the single nucleotide polymorphisms (SNPs) in , VKORC1, and CYP4F2. MLAs were used for identifying the significant genetic and clinical variables in predicting the poor anticoagulation status (ACS) and stable warfarin dose. Advanced computational methods (SNPs' deleteriousness and impact on protein destabilization, molecular dockings, and 200 ns molecular dynamics simulations) were employed for examining the influence of SNPs on structure and function. RESULTS: Machine learning algorithms revealed to be the most important predictor for both outcomes compared to the classical methods. Computational validation confirmed the altered structural activity, stability, and impaired functions of protein products of SNPs. Molecular docking and dynamics simulations revealed significant conformational changes with mutations R144C and I359L in . CONCLUSION: We evaluated various MLAs in predicting the critical outcome measures associated with warfarin and observed as the most critical predictor variable. The results of our study provide insight into the molecular basis of warfarin and the gene. A prospective study validating the MLAs is urgently needed.
The Application of Nucleic Acid Nanomaterials in the Treatment of Mitochondrial Dysfunction.
Yao L, Hai Q, Zhang T
Curr Drug Metab · 2023 · PMID 37317912 · Publisher ↗
Mitochondrial dysfunction is considered highly related to the development and progression of diseases, including cancer, metabolism disturbance, and neurodegeneration. Traditional pharmacological approach for mitochondri...
Mitochondrial dysfunction is considered highly related to the development and progression of diseases, including cancer, metabolism disturbance, and neurodegeneration. Traditional pharmacological approach for mitochondrial dysfunction treatment has off-target and dose-dependent side effects, which leads to the emergence of mitochondrial gene therapy by regulating coding or noncoding genes by using nucleic acid sequences such as oligonucleotides, peptide nucleic acids, rRNA, siRNA, etc. To avoid size heterogeneity and potential cytotoxicity of the traditional delivery vehicle like liposome, framework nucleic acids have shown promising potentials. First, special spatial structure like tetrahedron allows entry into cells without transfection reagents. Second, the nature of nucleic acid provides the editability of framework structure, more sites and methods for drug loading and targeted sequences linking, providing efficient transportation and accurate targeting to mitochondria. Third, controllable size leads a possibility to go through biological barrier such as the blood-brain barrier, reaching the central nervous system to reverse mitochondria-related neurodegeneration. In addition, it's biocompatibility and physiological environmental stability open up the possibility of in vivo treatments for mitochondrial dysfunction. Furthermore, we discuss the challenges and opportunities of framework nucleic acids-based delivery systems in mitochondrial dysfunction.
Structure of the Blood Brain Barrier and its Role in the Transporters for the Movement of Substrates across the Barriers.
Singh SA, Vellapandian C
Curr Drug Metab · 2023 · PMID 37291784 · Publisher ↗
For the brain to operate normally and to develop with structural integrity in addition to neuronal function, blood-brain barrier present in brain capillaries serves as a vital barrier mechanism. In addition to the transp...
For the brain to operate normally and to develop with structural integrity in addition to neuronal function, blood-brain barrier present in brain capillaries serves as a vital barrier mechanism. In addition to the transport barrier created by membranes, transporters, and vesicular processes, the structure and function of the BBB are summarised. The physical barrier is created by endothelial tight junctions. The permeability and transport of molecules between extracellular fluid and plasma are constrained by the presence of tight junctions between neighbouring endothelial cells. Each solute must pass through both membranes in the luminal and abluminal divisions. The functions of the neurovascular unit are described, with special emphasis on the pericytes, microglia, and astrocyte endfeet. The luminal membrane contains five separate facilitative transport mechanisms, each of which is exclusive to a few substrates. Nevertheless, the import of big-branched and aromatic neutral amino acids is facilitated by two key carriers (System L and y+) in the plasma membrane. It is asymmetrically present in both membranes. The sodium pump Na/K-ATPase is highly expressed in the abluminal membrane, where many Na dependent transport mechanisms move amino acids against its concentration gradient. The trojan horse strategy, which uses molecular tools to bind the medication and its formulations, is also preferred in drug delivery. The BBB's cellular structure, the transport systems unique to each substrate, and the necessity to identify transporters with changes that assist the transfer of various medications have all been changed in the current work. Nevertheless, to rule out the BBB passage for the new class of neuroactive medications, the mixing of traditional pharmacology and nanotechnology needs to be focused on outcomes that show promise.
Metabolism Pathways of Major Therapeutics for Treating Monkeypox Mono- and Co-infection with Human Immunodeficient Virus or SARS-CoV-2.
Yan D, Yan B
Curr Drug Metab · 2023 · PMID 37287302 · Full text
Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel histo...
Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, particularly of hydrolysis, phosphorylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.
Methods to Improve the Stability of Nucleic Acid-Based Nanomaterials.
Xie X, Ma W, Zhan Y … +3 more , Zhang Q, Wang C, Zhu H
Curr Drug Metab · 2023 · PMID 37264665 · Publisher ↗
Nucleic acid strands can be synthesized into various nucleic acid-based nanomaterials (NANs) through strict base pairing. The self-assembled NANs are programmable, intelligent, biocompatible, non-immunogenic, and non-cyt...
Nucleic acid strands can be synthesized into various nucleic acid-based nanomaterials (NANs) through strict base pairing. The self-assembled NANs are programmable, intelligent, biocompatible, non-immunogenic, and non-cytotoxic. With the rapid development of nanotechnology, the application of NANs in the biomedical fields, such as drug delivery and biological sensing, has attracted wide attention. However, the stability of NANs is often affected by the cation concentrations, enzymatic degradation, and organic solvents. This susceptibility to degradation is one of the most important factors that have restricted the application of NANs. NANs can be denatured or degraded under conditions of low cation concentrations, enzymatic presence, and organic solvents. To deal with this issue, a lot of methods have been attempted to improve the stability of NANs, including artificial nucleic acids, modification with specific groups, encapsulation with protective structures, etc. In this review, we summarized the relevant methods to have a deeper understanding of the stability of NANs.
State-of-the-art Application of Artificial Intelligence to Transporter-centered Functional and Pharmaceutical Research.
Yin J, You N, Li F … +3 more , Lu M, Zeng S, Zhu F
Curr Drug Metab · 2023 · PMID 37226790 · Publisher ↗
Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distr...
Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distribution, and excretion and are recognized as major determinants of drug safety and efficacy. Understanding transporter function is important for drug development and clarifying disease mechanisms. However, the experimental-based functional research on transporters has been challenged and hinged by the expensive cost of time and resources. With the increasing volume of relevant omics datasets and the rapid evolution of artificial intelligence (AI) techniques, next-generation AI is becoming increasingly prevalent in the functional and pharmaceutical research of transporters. Thus, a comprehensive discussion on the state-of-the-art application of AI in three cutting-edge directions was provided in this review, which included (a) transporter classification and function annotation, (b) structure discovery of membrane transporters, and (c) drug-transporter interaction prediction. This study provides a panoramic view of AI algorithms and tools applied to the field of transporters. It is expected to guide a better understanding and utilization of AI techniques for in-depth studies of transporter-centered functional and pharmaceutical research.
Factors Influencing ADME Properties of Drugs: Advances and Applications (Part I).
Zhang SQ, Chen F
Curr Drug Metab · 2023 · PMID 37190761 · Publisher ↗
Abstract loading — click title to view on PubMed.
Recent Advances in Novel Recombinant RNAs for Studying Post-transcriptional Gene Regulation in Drug Metabolism and Disposition.
Tu MJ, Yu AM
Curr Drug Metab · 2023 · PMID 37170982 · Full text
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/...
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/ pharmacodynamics (PK/PD) and further influence drug safety and therapeutic outcomes. ADME gene functions are controlled by diverse factors, such as genetic polymorphism, transcriptional regulation, and coadministered medications. MicroRNAs (miRNAs) are a superfamily of regulatory small noncoding RNAs that are transcribed from the genome to regulate target gene expression at the post-transcriptional level. The roles of miRNAs in controlling ADME gene expression have been demonstrated, and such miRNAs may consequently influence cellular drug metabolism and disposition capacity. Several types of miRNA mimics and small interfering RNA (siRNA) reagents have been developed and widely used for ADME research. In this review article, we first provide a brief introduction to the mechanistic actions of miRNAs in post-transcriptional gene regulation of drug-metabolizing enzymes, transporters, and transcription factors. After summarizing conventional small RNA production methods, we highlight the latest advances in novel recombinant RNA technologies and applications of the resultant bioengineered RNA (BioRNA) agents to ADME studies. BioRNAs produced in living cells are not only powerful tools for general biological and biomedical research but also potential therapeutic agents amenable to clinical investigations.
Comparative Pharmacokinetics of Scoparone and its Metabolite Scopoletin in Normal and ANIT-induced Intrahepatic Cholestatic Rats.
Tian Q, Jin H, Huo X … +8 more , Zhao Y, Wu W, Xu L, Wang Y, Yang X, Sun C, Deng S, Shu X
Curr Drug Metab · 2023 · PMID 37165497 · Publisher ↗
BACKGROUND: Scoparone, the principal natural active ingredient of (Yin Chen), can effectively treat cholestatic diseases, but the pharmacokinetic properties of scoparone are rarely studied in intrahepatic cholestatic ra...
BACKGROUND: Scoparone, the principal natural active ingredient of (Yin Chen), can effectively treat cholestatic diseases, but the pharmacokinetic properties of scoparone are rarely studied in intrahepatic cholestatic rats. OBJECTIVE: A sensitive and rapid LC-MS/MS method was established to detect scoparone and its metabolite of scopoletin in rat plasma and then compare their plasma pharmacokinetic differences between the normal and ANITinduced cholestasis rats. METHODS: Positive ionization was used to separate scoparone and scopoletin using acetonitrile and 0.1 % formic acid water as the mobile phase on a Hypersil ODS-BP column. RESULTS: The calibration curves presented good linearity (R=0.9983 and 0.9989) in the concentration range of 10- 10000 ng/mL and 0.5-500 ng/mL for scoparone and scopoletin, respectively. The precision of ≤ 9.4% and the accuracy ranged from -6.4% to 6.8% were recorded over three validation runs, and the recovery was higher than 83.9%. Under different storage conditions, scoparone and scopoletin were stable. Therefore, we studied the pharmacokinetic properties of scoparone and scopoletin in rats after a single oral administration with the above method. According to the results, the pharmacokinetic parameters of AUC, t, and C values of scoparone in the ANIT group were increased by 106%, 75%, and 44%, respectively, while these values of scopoletin were increased by 142%, 62%, and 65%. CONCLUSION: The findings indicated that the pharmacokinetic properties of scoparone and scopoletin were significantly different between the normal and ANIT-induced cholestasis rats, which suggested that the clinical application dosage of scoparone should be adjusted according to the liver function of patients.
Physiologically Based Pharmacokinetic Model for Older Adults and Its Application in Geriatric Drug Research.
Wu X, Sia JEV, Hai M … +4 more , Lai X, Li H, Cui C, Liu D
Curr Drug Metab · 2023 · PMID 37165496 · Publisher ↗
Drug-related adverse events are higher in older patients than in non-older patients, increasing the risk of medication and reducing compliance. Aging is accompanied by a decline in physiological functions and metabolic w...
Drug-related adverse events are higher in older patients than in non-older patients, increasing the risk of medication and reducing compliance. Aging is accompanied by a decline in physiological functions and metabolic weakening. Most tissues and organs undergo anatomical and physiological changes that may affect the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of drugs. Clinical trials are the gold standard for selecting appropriate dosing regimens. However, older patients are generally underrepresented in clinical trials, resulting in a lack of evidence for establishing an optimal dosing regimen for older adults. The physiologically based pharmacokinetic (PBPK) model is an effective approach to quantitatively describe the absorption, distribution, metabolism, and excretion of drugs in older adults by integrating physiological parameters, drug physicochemical properties, and preclinical or clinical PK data. The PBPK model can simulate the PK/PD characteristics of clinical drugs in different scenarios, ultimately compensating for inadequate clinical trial data in older adults, and is recommended by the Food and Drug Administration for clinical pharmacology studies in older adults. This review describes the effects of physiological changes on the PK/PD process in older adults and summarises the research progress of PBPK models. Future developments of PBPK models are also discussed, together with the application of PBPK models in older adults, aiming to assist the development of clinical study strategies in older adults.
Global Xenobiotic Profiling of Rat Plasma Using Untargeted Metabolomics and Background Subtraction-Based Approaches: Method Evaluation and Comparison.
Jiang X, Chen S, Zhu M … +1 more , Wu C
Curr Drug Metab · 2023 · PMID 37157207 · Publisher ↗
BACKGROUND: Global xenobiotic profiling (GXP) is to detect and structurally characterize all xenobiotics in biological samples using mainly liquid chromatography-high resolution mass spectrometry (LC-HRMS) based methods....
BACKGROUND: Global xenobiotic profiling (GXP) is to detect and structurally characterize all xenobiotics in biological samples using mainly liquid chromatography-high resolution mass spectrometry (LC-HRMS) based methods. GXP is highly needed in drug metabolism study, food safety testing, forensic chemical analysis, and exposome research. For detecting known or predictable xenobiotics, targeted LC-HRMS data processing methods based on molecular weights, mass defects and fragmentations of analytes are routinely employed. For profiling unknown xenobiotics, untargeted and LC-HRMS based metabolomics and background subtraction-based approaches are required. OBJECTIVE: This study aimed to evaluate the effectiveness of untargeted metabolomics and the precise and thorough background subtraction (PATBS) in GXP of rat plasma. METHODS: Rat plasma samples collected from an oral administration of nefazodone (NEF) or (Gancao, GC) were analyzed by LC-HRMS. NEF metabolites and GC components in rat plasma were thoroughly searched and characterized processing LC-HRMS datasets using targeted and untargeted methods. RESULTS: PATBS detected 68 NEF metabolites and 63 GC components, while the metabolomic approach (MS-DIAL) found 67 NEF metabolites and 60 GC components in rat plasma. The two methods found 79 NEF metabolites and 80 GC components with 96% and 91% successful rates, respectively. CONCLUSION: Metabolomics methods are capable of GXP and measuring alternations of endogenous metabolites in a group of biological samples, while PATBS is more suited for sensitive GXP of a single biological sample. A combination of metabolomics and PATBS approaches can generate better results in the untargeted profiling of unknown xenobiotics.
The Metabolic Pathways and Products of Ten Alkaloids in Sanwujiao Pills from Eight Organs of Mice by UHPLC-Q-TOF-MS/MS.
Pei WH, Huang YF, Xie Y … +3 more , Qu Y, He F, Zhou H
Curr Drug Metab · 2023 · PMID 37151055 · Publisher ↗
BACKGROUND: Sanwujiao pill (SWJP) is a Chinese herbal preparation widely used in China. It is an essential medicine for treating rheumatism and blood stasis. However, its safety in clinical use has always been the focus...
BACKGROUND: Sanwujiao pill (SWJP) is a Chinese herbal preparation widely used in China. It is an essential medicine for treating rheumatism and blood stasis. However, its safety in clinical use has always been the focus of patients because it contains toxic herbs of Debx. and Kom. OBJECTIVE: To further reveal the pharmaceutical and toxic effect substances and the action mechanism of SWJPs, the metabolites and their pathways of ten alkaloids (AAs) in the preparation at different time points after oral administration in eight organs of mice were investigated. METHOD: The biosamples were investigated by a four-step strategy of UPLC-Q-TOF-MS /MS technology. RESULTS: Aconitine (AC), mesaconitine (MA), and hypaconitine (HA) were not detected in any organs. The highest concentrations of the other seven AAs occurred at 0.5 h. Yunaconitine (YAC) was not detected in the brain; all seven AAs had the lowest concentration in the brain, and the metabolism was slow in the stomach. Twelve predicted metabolites were identified, the kidney and stomach were their primary distribution locations, and the most metabolites were found at 0.5h. The main metabolic pathways of the ten AAs were demethylation, deethylation, deoxygenation, hydroxylation, and deacetylation. CONCLUSION: This is the first report about the metabolism of ten AAs in SWJPs in mice. Significantly, the metabolic pathways and products of four hidden toxic AAs were analyzed for the first time. The results were of great significance for the safety and effectiveness of SWJPs in clinical application.
LC-Q-TOF/MS-based Fragmentation Behavior Study and Metabolites Identification of Nine Benzodiazepines.
Zhou S, Song X, Fang P … +5 more , Xu J, Liu S, Zheng T, Wu G, Wu L
Curr Drug Metab · 2023 · PMID 37114779 · Publisher ↗
BACKGROUND: Benzodiazepines (BZDs) are compounds that contain one diazepine ring and two benzene rings, and are widely used to treat central nervous system diseases. However, drug abuse and BZDs' illegal addition may aff...
BACKGROUND: Benzodiazepines (BZDs) are compounds that contain one diazepine ring and two benzene rings, and are widely used to treat central nervous system diseases. However, drug abuse and BZDs' illegal addition may affect normal life and even lead to grave social harm. As BZDs may be metabolized and eliminated quickly, it is of great theoretical and practical significance to clarify their metabolic profile. OBJECTIVE: In this paper, LC-Q-TOF/MS-based fragmentation behavior has been investigated for nine benzodiazepine drugs available and widely used in clinical treatment (diazepam, nitrazepam, clonazepam, oxazepam, lorazepam, alprazolam, estazolam, triazolam, and midazolam), and their metabolic profile has been studied by using in vitro human liver microsomal incubation. METHODS: A regular human liver microsomal system was used to investigate the potential biotransformation of the nine benzodiazepines in vitro, and an LC-Q/TOF-MS was used to perform fragmentation behavior studies and metabolite identification. RESULTS: As a result, characteristic fragmentation pathway and diagnostic fragment ions of the nine BZDs were analyzed, and 19 metabolites of the 9 benzodiazepines were found and identified, with glucuronidation and hydroxylation considered as their most important metabolic pathways. CONCLUSION: These experimental data add to our knowledge of the nine benzodiazepine drugs and their metabolism study, which could provide useful information and evidence of their in vivo metabolic profile prediction and help promote their monitoring in both clinical use and social/illegal abuse.
Folate Targeting Peptide Conjugates for Inflammatory Response Suppression.
Ruff E, Poh S
Curr Drug Metab · 2023 · PMID 37114778 · Publisher ↗
BACKGROUND AND OBJECTIVE: Protein kinases known as mitogen-activated protein kinases (MAPKs) are responsible for regulating a wide variety of physiological cell responses by generating and release of inflammatory mediato...
BACKGROUND AND OBJECTIVE: Protein kinases known as mitogen-activated protein kinases (MAPKs) are responsible for regulating a wide variety of physiological cell responses by generating and release of inflammatory mediators. Suppressing these inflammatory mediators can be utilized to control the propagation of inflammation. During the course of this research, we created folate-targeted MK2 inhibitor conjugates and analyzed the antiinflammatory effects of these compounds. METHODS: Using RAW264.7 cells, which are generated from murine macrophages, as an in vitro model. We synthesize and evaluated a folate linked peptide MK2 inhibitor. The cytotoxicity was assessed using the ELISA kits, CCK- 8 test kit, NO concentration and inflammatory factors TNF-, IL-1, and IL-6. RESULTS: The cytotoxicity assay results suggested that the concentration for MK2 inhibitors less than 50.0 μM be non-toxic. The ELISA Kits also demonstrated that MK2 peptide inhibitor treatment significantly decreased the content of NO, TNF-, IL-1, and IL-6 in LPS-stimulated RAW264.7 cells. It was also demonstrated that a folate-targeted MK2 inhibitor was more effective than a non-targeted inhibitor. CONCLUSION: This experiment demonstrates that LPS-induced macrophages can produce oxidative stress and inflammatory mediators. According to our research, pro-inflammatory mediators can be reduced by targeting folate receptor- positive (FR+) macrophages with an FR-linked anti-inflammatory MK2 peptide inhibitor in vitro, and the uptake was FR-specific.
Pharmacokinetic Drug-Drug Interactions Involving Antiretroviral Agents: An Update.
Yu X, Zhao L, Yuan Z … +1 more , Li Y
Curr Drug Metab · 2023 · PMID 37076461 · Publisher ↗
Antiretroviral therapy is the recognized treatment for human immunodeficiency virus (HIV) infection involving several antiviral agents. Even though highly active antiretroviral therapy has been proven to be very effectiv...
Antiretroviral therapy is the recognized treatment for human immunodeficiency virus (HIV) infection involving several antiviral agents. Even though highly active antiretroviral therapy has been proven to be very effective in suppressing HIV replication, the antiretroviral drugs, belonging to different pharmacological classes, present quite complex pharmacokinetic properties such as extensive drug metabolism and transport by membrane-associated drug carriers. Moreover, due to uncomplications or complications in HIV-infected populations, an antiretroviralbased multiple-drug coadministration therapy strategy is usually applied for treatment effect, thus raising the possibility of drug-drug interactions between antiretroviral drugs and common drugs such as opioids, stains, and hormonal contraceptives. Herein, thirteen classical antiretroviral drugs approved by US Food and Drug Administration were summarized. Besides, relative drug metabolism enzymes and transporters known to interact with those antiretroviral drugs were detailed and described. Furthermore, one after the summarized antiretroviral drugs, the drug-drug interactions between two antiretroviral drugs or antiretroviral drug - conventional medical drugs of the past decade were discussed and summarized. This review is intended to deepen the pharmacological understanding of antiretroviral drugs and promote more secure clinical applications for antiretroviral drugs to treat HIV.
Factors Influencing ADME Properties of Therapeutic Antisense Oligonucleotides: Physicochemical Characteristics and Beyond.
Jiang R, Hooshfar S, Rebecca Eno M … +3 more , Yun C, Sonego Zimmermann E, Shinkyo R
Curr Drug Metab · 2023 · PMID 37076460 · Publisher ↗
Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventio...
Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution, metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore, thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar chemistry, conjugation approaches, sites and routes of administration, are the principal determinants of ADME and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs. We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe