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Biomedicines Jan 2022Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential... (Review)
Review
Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood-brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP's limitations, including bioavailability and blood-brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.
PubMed: 35052833
DOI: 10.3390/biomedicines10010154 -
Biochemical Pharmacology Jan 2014Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE)... (Review)
Review
Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE) after its administration to the body. Following a brief introduction as to why knowledge of the PK properties of an NCE is critical to its selection as a lead candidate in a drug discovery program and/or its use as a functional research tool, the present article presents an overview of PK principles, including practical guidelines for conducting PK studies as well as the equations required for characterizing and understanding the PK of an NCE and its metabolite(s). A review of the determination of in vivo PK parameters by non-compartmental and compartmental methods is followed by a brief overview of allometric scaling. Compound absorption and permeability are discussed in the context of intestinal absorption and brain penetration. The volume of distribution and plasma protein and tissue binding are covered as is the clearance (systemic, hepatic, renal, biliary) of both small and large molecules. A section on metabolite kinetics describes how to estimate the PK parameters of a metabolite following administration of an NCE. Lastly, mathematical models used to describe pharmacodynamics (PD), the relationship between the NCE/compound concentration at the site of action and the resulting effect, are reviewed and linked to PK models in a section on PK/PD.
Topics: Animals; Half-Life; Humans; Intestinal Absorption; Metabolic Clearance Rate; Permeability; Pharmaceutical Preparations; Tissue Distribution
PubMed: 24055064
DOI: 10.1016/j.bcp.2013.09.007 -
Analytical Chemistry May 2023Targeted metabolomics has been broadly used for metabolite measurement due to its good quantitative linearity and simple metabolite annotation workflow. However,...
Targeted metabolomics has been broadly used for metabolite measurement due to its good quantitative linearity and simple metabolite annotation workflow. However, metabolite interference, the phenomenon where one metabolite generates a peak in another metabolite's MRM setting (Q1/Q3) with a close retention time (RT), may lead to inaccurate metabolite annotation and quantification. Besides isomeric metabolites having the same precursor and product ions that may interfere with each other, we found other metabolite interferences as the result of inadequate mass resolution of triple-quadruple mass spectrometry and in-source fragmentation of metabolite ions. Characterizing the targeted metabolomics data using 334 metabolite standards revealed that about 75% of the metabolites generated measurable signals in at least one other metabolite's MRM setting. Different chromatography techniques can resolve 65-85% of these interfering signals among standards. Metabolite interference analysis combined with the manual inspection of cell lysate and serum data suggested that about 10% out of ∼180 annotated metabolites were mis-annotated or mis-quantified. These results highlight that a thorough investigation of metabolite interference is necessary for accurate metabolite measurement in targeted metabolomics.
Topics: Chromatography, Liquid; Tandem Mass Spectrometry; Metabolomics; Reference Standards; Ions
PubMed: 37155916
DOI: 10.1021/acs.analchem.3c00804 -
3 Biotech Nov 2023In this study, the effects of cocaine metabolite, benzoylecgonine, commonly found in wastewater on hydrogen production were investigated using microbial electrolysis...
UNLABELLED
In this study, the effects of cocaine metabolite, benzoylecgonine, commonly found in wastewater on hydrogen production were investigated using microbial electrolysis cells. Benzoylecgonine dissolved in synthetic urine and human urine containing benzoylecgonine were inoculated to evaluate hydrogen production performance in microbial electrolysis cells. Microbial electrolysis cells were inoculated with synthetic urine and human urine containing the cocaine metabolite benzoylecgonine for hydrogen gas production performance. Gas production was observed and measured daily by gas chromatography. GC-MS was used to analyze the compounds found in human urine before and after operation in microbial electrolysis cells. The metabolite's pH values and optical density in microbial electrolysis cells were analyzed spectrophotometrically. Hydrogen gas was successfully produced in microbial electrolysis cells (~ 5.5 mL) at the end of the 24th day in the presence of benzoylecgonine in synthetic urine. Human urine containing benzoylecgonine also generated hydrogen in microbial electrolysis cells. In conclusion, microbial electrolysis cells can be used to remove cocaine metabolites from contaminated wastewater generating hydrogen gas.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03805-7.
PubMed: 37920191
DOI: 10.1007/s13205-023-03805-7 -
Toxicological Sciences : An Official... Aug 2021Impregnating military uniforms and outdoor clothing with the insecticide permethrin is an approach to reduce exposure to insect borne diseases and to repel pests and...
Impregnating military uniforms and outdoor clothing with the insecticide permethrin is an approach to reduce exposure to insect borne diseases and to repel pests and disease vectors such as mosquitos and sandflies, but the practice exposes wearers to prolonged dermal exposure to the pesticide. Key metabolite(s) from a low dose dermal exposure of permethrin were identified using accelerator mass spectrometry. Metabolite standards were synthesized and a high performance liquide chromatography (HPLC) elution protocol to separate individual metabolites in urine was developed. Six human subjects were exposed dermally on the forearm to 25 mg of permethrin containing 1.0 µCi of 14C for 8 h. Blood, saliva and urine samples were taken for 7d. Absorption/elimination rates and metabolite concentrations varied by individual. Average absorption was 0.2% of the dose. Serum concentrations rose until 12-24 h postdermal application then rapidly declined reaching predose levels by 72 h. Maximum saliva excretion occurred 6 h postdosing. The maximum urinary excretion rate occurred during 12-24 h; average elimination half-life was 56 h. 3-Phenoxybenzyl alcohol glucuronide was the most abundant metabolite identified when analyzing elution fractions, but most of the radioactivity was in still more polar fractions suggesting extensive degradative metabolism and for which there were no standards. Analyses of archived urine samples with the ultra performance liquid chromatography-accelerator mass spectrometry-mass spectrometry (UPLC-AMS-MS) system isolated a distinct polar metabolite but it was much diminished from the previous analyses a decade earlier.
Topics: Animals; Biomarkers; Chromatography, High Pressure Liquid; Humans; Insecticides; Mass Spectrometry; Permethrin
PubMed: 34460930
DOI: 10.1093/toxsci/kfab082 -
Expert Opinion on Drug Metabolism &... Sep 2010Due to growing concerns over toxic or active metabolites, significant efforts have been focused on qualitative identification of potential in vivo metabolites from in... (Review)
Review
IMPORTANCE OF THE FIELD
Due to growing concerns over toxic or active metabolites, significant efforts have been focused on qualitative identification of potential in vivo metabolites from in vitro data. However, limited tools are available to quantitatively predict their human exposures.
AREAS COVERED IN THIS REVIEW
Theory of clearance predictions and metabolite kinetics is reviewed together with supporting experimental data. In vitro and in vivo data of known circulating metabolites and their parent drugs were collected and the predictions of in vivo exposures of the metabolites were evaluated.
WHAT THE READER WILL GAIN
The theory and data reviewed will be useful in early identification of human metabolites that will circulate at significant levels in vivo and help in designing in vivo studies that focus on characterization of metabolites. It will also assist in rationalization of metabolite-to-parent ratios used as markers of specific enzyme activity.
TAKE HOME MESSAGE
The relative importance of a metabolite in comparison to the parent compound as well as other metabolites in vivo can only be predicted using the metabolite's in vitro formation and elimination clearances, and the in vivo disposition of a metabolite can only be rationalized when the elimination pathways of that metabolite are known.
Topics: Drug Evaluation; Enzyme Activation; Humans; Microsomes, Liver; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 20557268
DOI: 10.1517/17425255.2010.497487 -
Cells Sep 2022The metabolites produced by the gut microbiota have been reported as crucial agents against obesity; however, their key targets have not been revealed completely in... (Meta-Analysis)
Meta-Analysis
The metabolites produced by the gut microbiota have been reported as crucial agents against obesity; however, their key targets have not been revealed completely in complex microbiome systems. Hence, the aim of this study was to decipher promising prebiotics, probiotics, postbiotics, and more importantly, key target(s) via a network pharmacology approach. First, we retrieved the metabolites related to gut microbes from the gutMGene database. Then, we performed a meta-analysis to identify metabolite-related targets via the similarity ensemble approach (SEA) and SwissTargetPrediction (STP), and obesity-related targets were identified by DisGeNET and OMIM databases. After selecting the overlapping targets, we adopted topological analysis to identify core targets against obesity. Furthermore, we employed the integrated networks to microbiota-substrate-metabolite-target (MSMT) via R Package. Finally, we performed a molecular docking test (MDT) to verify the binding affinity between metabolite(s) and target(s) with the Autodock 1.5.6 tool. Based on holistic viewpoints, we performed a filtering step to discover the core targets through topological analysis. Then, we implemented protein-protein interaction (PPI) networks with 342 overlapping target, another subnetwork was constructed with the top 30% degree centrality (DC), and the final core networks were obtained after screening the top 30% betweenness centrality (BC). The final core targets were IL6, AKT1, and ALB. We showed that the three core targets interacted with three other components via the MSMT network in alleviating obesity, i.e., four microbiota, two substrates, and six metabolites. The MDT confirmed that equol (postbiotics) converted from isoflavone (prebiotics) via (probiotics) can bind the most stably on IL6 (target) compared with the other four metabolites (3-indolepropionic acid, trimethylamine oxide, butyrate, and acetate). In this study, we demonstrated that the promising substate (prebiotics), microbe (probiotics), metabolite (postbiotics), and target are suitable for obsesity treatment, providing a microbiome basis for further research.
Topics: Butyrates; Equol; Gastrointestinal Microbiome; Humans; Interleukin-6; Molecular Docking Simulation; Network Pharmacology; Obesity; Prebiotics; Probiotics
PubMed: 36139478
DOI: 10.3390/cells11182903 -
Arzneimittel-Forschung 2009In recent years, the assessment of metabolite pharmacokinetic data has been increasingly on the rise in several types of clinical pharmacology studies including... (Review)
Review
In recent years, the assessment of metabolite pharmacokinetic data has been increasingly on the rise in several types of clinical pharmacology studies including bioavailability/bioequivalence assessments of drug formulations. While the importance of pharmacokinetic data of metabolite(s) are well accepted, there appears to be reluctance on the part of scientific community to use such data in a prospective manner in the establishment of bioavailability/bioequivalence of marketed products and/or drugs in development. This review highlights the current trends that suggest that metabolite(s) data are being considered with or without the parent pharmacokinetic data in bioavailability/bioequivalence studies with numerous case studies. Also, some useful considerations from both bioanalytical and pharmacokinetic perspectives are proposed.
Topics: Biological Availability; Data Interpretation, Statistical; Humans; Legislation, Drug; Pharmaceutical Preparations; Pharmacokinetics; Therapeutic Equivalency
PubMed: 19517891
DOI: 10.1055/s-0031-1296380 -
Brazilian Journal of Biology = Revista... 2021Since the classic studies of Alexander Flemming, Penicillium strains have been known as a rich source of antimicrobial substances. Recent studies have identified novel...
Since the classic studies of Alexander Flemming, Penicillium strains have been known as a rich source of antimicrobial substances. Recent studies have identified novel metabolites produced by Penicillium sclerotiorum that have antibacterial, antifouling and pharmaceutical activities. Here, we report the isolation of a P. sclerotiorum (LM 5679) from Amazonian soil and carry out a culture-based study to determine whether it can produce any novel secondary metabolite(s) that are not thus-far reported for this genus. Using a submerged culture system, secondary metabolites were recovered by solvent extract followed by thin-layer chromatography, nuclear magnetic resonance, and mass spectroscopy. One novel secondary metabolite was isolated from P. sclerotiorum (LM 5679); the phenolic compound 5-pentadecyl resorcinol widely known as an antifungal, that is produced by diverse plant species. This metabolite was not reported previously in any Penicillium species and was only found once before in fungi (that time, in a Fusarium). Here, we discuss the known activities of 5-pentadecyl resorcinol in the context of its mode-of-action as a hydrophobic (chaotropicity-mediated) stressor.
Topics: Anti-Bacterial Agents; Antifungal Agents; Penicillium; Resorcinols
PubMed: 34133562
DOI: 10.1590/1519-6984.241863 -
Biomedical Chromatography : BMC Jan 2010The introduction of irinotecan has revolutionized the applicability of camptothecins as predominant topoisomerase I inhibitor for anti-cancer therapy. The potent... (Review)
Review
The introduction of irinotecan has revolutionized the applicability of camptothecins as predominant topoisomerase I inhibitor for anti-cancer therapy. The potent anti-tumor activity of irinotecan is due to rapid formation of an in vivo active metabolite, SN-38. Therefore, irinotecan is considered as a pro-drug to generate SN-38. Over the past decade, side-by-side with the clinical advancement of the use of irinotecan in the oncology field, a plethora of bioanalytical methods have been published to quantify irinotecan, SN-38 and other metabolites. Because of the availability of HPLC, LC-MS and LC-MS/MS methods, the pharmacokinetic profiling of irinotecan and its metabolites has been accomplished in multiple species, including cancer patients. The developed assays continue to find use in the optimization of newly designed delivery systems with regard to pharmacokinetics to promote safe and effective use of either irinotecan or SN-38. This review intends to: firstly, provide an exhaustive compilation of the published assays for irinotecan, SN-38 and other metabolite(s) of irinotecan, as applicable; secondly, to enumerate the validation parameters and applicable conclusions; and thirdly, provide some recent perspectives in the clinical pharmacology arena pertaining to efflux transporters, pediatric profiling, role of kidney function in defining toxicity, drug-drug interaction potential of irinotecan, etc.
Topics: Antineoplastic Agents, Phytogenic; Camptothecin; Chromatography, High Pressure Liquid; Humans; Irinotecan; Prodrugs; Tandem Mass Spectrometry; Topoisomerase I Inhibitors
PubMed: 19852077
DOI: 10.1002/bmc.1345