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Expert Opinion on Drug Metabolism &... Jun 2022Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes... (Review)
Review
INTRODUCTION
Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes in absorption, distribution, excretion and metabolization. Hepatic drug metabolism might be altered due to changes in hepatic blood flow, drug metabolizing protein availability, and protein binding. The purpose of this review is to examine evidence on whether hepatic drug metabolism is significantly affected in septic patients, and to provide insights in the need for future research.
AREAS COVERED
This review describes the effect of sepsis on hepatic drug metabolism in humans. Clinical trials, pathophysiological background information and example drug groups are further discussed. The literature search has been conducted in Embase, Medline ALL Ovid, and Cochrane CENTRAL register of trials.
EXPERT OPINION
Limited research has been conducted on drug metabolism in the sepsis population, with some trials having researched healthy individuals using endotoxin injections. Notwithstanding this limitation, hepatic drug metabolism seems to be decreased for certain drugs in sepsis. More research on the pharmacokinetic behavior of hepatic metabolized drugs in sepsis is warranted, using inflammatory biomarkers, hemodynamic changes, mechanical ventilation, organ support, and catecholamine infusion as possible confounders.
Topics: Critical Illness; Humans; Liver; Sepsis
PubMed: 35912845
DOI: 10.1080/17425255.2022.2106215 -
Journal of Pharmaceutical Sciences Feb 2016Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks.... (Review)
Review
Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be used to construct physiologically based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been used to study cytotoxicity and perturbation of biological processes by drugs and hepatically generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model were used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction.
Topics: Animals; Biological Transport; Cell Culture Techniques; Chemical and Drug Induced Liver Injury; Drug Liberation; Hepatocytes; Humans; Metabolic Networks and Pathways; Pharmaceutical Preparations; Tissue Distribution
PubMed: 26869411
DOI: 10.1016/j.xphs.2015.11.008 -
Biochimica Et Biophysica Acta Sep 2016The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR... (Review)
Review
The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR was originally identified to regulate drug-metabolizing enzymes and transporters. During the last ten years it has become clear that PXR harbors broader functions. Evidence obtained both in experimental animals and humans indicate that ligand-activated PXR regulates hepatic glucose and lipid metabolism and affects whole body metabolic homeostasis. Currently, the consequences of PXR activation on overall metabolic health are not yet fully understood and varying results on the effect of PXR activation or knockout on metabolic disorders and weight gain have been published in mouse models. Rifampicin and St. John's wort, the prototypical human PXR agonists, impair glucose tolerance in healthy volunteers. Chronic exposure to PXR agonists could potentially represent a risk factor for diabetes and metabolic syndrome. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Topics: Animals; Diabetes Mellitus; Gene Expression Regulation; Gluconeogenesis; Glucose; Glycolysis; Humans; Hypericum; Inactivation, Metabolic; Lipogenesis; Liver; Metabolic Syndrome; Pregnane X Receptor; Receptors, Steroid; Rifampin; Signal Transduction
PubMed: 27041449
DOI: 10.1016/j.bbagrm.2016.03.012 -
Current Drug Targets 2018MiR-17-92 cluster is coded by MIR17HG in chromosome 13, which is highly conserved in vertebrates. Published literatures have proved that miR-17-92 cluster critically... (Review)
Review
BACKGROUND
MiR-17-92 cluster is coded by MIR17HG in chromosome 13, which is highly conserved in vertebrates. Published literatures have proved that miR-17-92 cluster critically regulates tumorigenesis and metastasis. Recent researches showed that the miR-17-92 cluster also plays novel functions in the endocrine system.
OBJECTIVE
To summarize recent findings on the physiological and pathological roles of miR-17-92 cluster in bone, lipid and glucose metabolisms.
RESULTS
MiR-17-92 cluster plays significant regulatory roles in bone development and metabolism through regulating the differentiation and function of osteoblasts and osteoclasts. In addition, miR-17- 92 cluster is nearly involved in every aspect of lipid metabolism. Last but not the least, the miR-17-92 cluster is closely bound up with pancreatic beta cell function, development of type 1 diabetes and insulin resistance. However, whether miR-17-92 cluster is involved in the communication among bone, fat and glucose metabolisms remains unknown.
CONCLUSION
Growing evidence indicates that miR-17-92 cluster plays significant roles in bone, lipid and glucose metabolisms through a variety of signaling pathways. Fully understanding its modulating mechanisms may necessarily facilitate to comprehend the clinical and molecule features of some metabolic disorders such as osteoporosis, arthrosclerosis and diabetes mellitus. It may provide new drug targets to prevent and cure these disorders.
Topics: Animals; Bone and Bones; Endocrine System; Gene Expression Regulation; Glucose; Homeostasis; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; MicroRNAs; Osteogenesis; RNA, Long Noncoding; Signal Transduction
PubMed: 29149826
DOI: 10.2174/1389450118666171117125319 -
Biochimica Et Biophysica Acta.... Jun 2021Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by... (Review)
Review
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.
Topics: Animals; Constitutive Androstane Receptor; Humans; Inactivation, Metabolic; Liver Diseases; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Xenobiotics
PubMed: 33600998
DOI: 10.1016/j.bbadis.2021.166101 -
Frontiers in Immunology 2024Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past... (Review)
Review
Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
Topics: Humans; Fructose; Neoplasms; Tumor Microenvironment; Animals; Cellular Reprogramming; Energy Metabolism; Metabolic Reprogramming
PubMed: 38711514
DOI: 10.3389/fimmu.2024.1375461 -
Drug Metabolism Reviews Aug 2017Metabolism in the eye for any species, laboratory animals or human, is gaining rapid interest as pharmaceutical scientists aim to treat a wide range of so-called... (Review)
Review
Metabolism in the eye for any species, laboratory animals or human, is gaining rapid interest as pharmaceutical scientists aim to treat a wide range of so-called incurable ocular diseases. Over a period of decades, reports of metabolic activity toward various drugs and biochemical markers have emerged in select ocular tissues of animals and humans. Ocular cytochrome P450 (P450) enzymes and transporters have been recently reviewed. However, there is a dearth of collated information on non-P450 drug metabolizing enzymes in eyes of various preclinical species and humans in health and disease. In an effort to complement ocular P450s and transporters, which have been well reviewed in the literature, this review is aimed at presenting collective information on non-P450 oxidative, hydrolytic, and conjugative ocular drug metabolizing enzymes. Herein, we also present a list of xenobiotics or drugs that have been reported to be metabolized in the eye.
Topics: Animals; Cytochrome P-450 Enzyme System; Eye; Humans; Oxidation-Reduction; Xenobiotics
PubMed: 28438049
DOI: 10.1080/03602532.2017.1322609 -
Drug Metabolism and Disposition: the... Oct 2020Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental... (Review)
Review
Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental systems for the evaluation of enteric metabolism and drug interaction potential. Enteric nuclear receptors include vitamin D receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, liver X receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor. Enteric drug metabolizing enzyme pathways include both cytochrome P450 (P450) and non-P450 drug metabolizing enzymes based on gene expression, proteomics, and activity. Both uptake and efflux transporters are present in the small intestine, with P-glycoprotein found to be responsible for most drug-drug and food-drug interactions. The cell-based in vitro enteric systems reviewed are 1) immortalized cell line model: the human colon adenocarcinoma (Caco-2) cells; 2) human stem cell-derived enterocyte models: stem cell enteric systems, either from intestinal crypt cells or induced pluripotent stem cells; and 3) primary cell models: human intestinal slices, cryopreserved human enterocytes, permeabilized cofactor-supplemented (MetMax) cryopreserved human enterocytes, and cryopreserved human intestinal mucosa. The major deficiency with both immortalized cell lines and stem cell-derived enterocytes is that drug metabolizing enzyme activities, although they are detectable, are substantially lower than those for the intestinal mucosa in vivo. Human intestine slices, cryopreserved human enterocytes, MetMax cryopreserved human enterocytes, and cryopreserved human intestinal mucosa retain robust enteric drug metabolizing enzyme activity and represent appropriate models for the evaluation of metabolism and metabolism-dependent drug interaction potential of orally administered xenobiotics including drugs, botanical products, and dietary supplements. SIGNIFICANCE STATEMENT: Enteric drug metabolism plays an important role in the bioavailability and metabolic fate of orally administered drugs as well as in enteric drug-drug and food-drug interactions. The current status of key enteric drug metabolism and disposition pathways and in vitro human cell-based enteric experimental systems for the evaluation of the metabolism and drug interaction potential of orally administered substances is reviewed.
Topics: Administration, Oral; Biological Availability; Biological Products; Caco-2 Cells; Cryopreservation; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Drug Interactions; Enterocytes; Humans; Intestinal Mucosa; Metabolic Clearance Rate; Receptors, Cytoplasmic and Nuclear; Species Specificity; Stem Cells; Xenobiotics
PubMed: 32636209
DOI: 10.1124/dmd.120.000053 -
Advances in Experimental Medicine and... 2022Sphingolipids are the major lipid components on cellular membranes especially on lipid raft regions, intermediating various important biological functions for eukaryotic...
Sphingolipids are the major lipid components on cellular membranes especially on lipid raft regions, intermediating various important biological functions for eukaryotic cells. Sphingolipid metabolism pathways can utilize sugar, protein, nucleic acid, and other metabolites participating lipid transport in the circulation, play an essential role in maintaining cell homeostasis and are related to a variety of different diseases including lysosomal storage disorders (LSDs), Gaucher disease, etc. The dynamic balance of sphingolipid levels in organisms is regulated by a series of sphingolipid synthases, hydrolases, and metabolic enzymes, such as sphingomyelinase (SMase), sphingomyelin synthase (SMS), serine palmitoyltransferase (SPT), ceramide synthase (CerS), glucosylceramide synthase (GCS), etc. Thus, sphingolipids and its related enzymes are potential targets for drug discoveries and receive great research interests by medicinal chemist. In this chapter, we will discuss the relationship between sphingolipids and the regulating enzymes involved in sphingolipid metabolisms, and systematically summarize the advances in the development of new drugs in the field.
Topics: Ceramides; Drug Development; Homeostasis; Lipid Metabolism; Serine C-Palmitoyltransferase; Sphingolipids
PubMed: 35503181
DOI: 10.1007/978-981-19-0394-6_12 -
Journal of Clinical Pharmacology Oct 2016FDA recommendations to manage polymorphic CYP-mediated drug-drug interactions (DDIs) and gene-drug interactions (GDIs) are typically similar. However, DDIs may not...
FDA recommendations to manage polymorphic CYP-mediated drug-drug interactions (DDIs) and gene-drug interactions (GDIs) are typically similar. However, DDIs may not always reliably predict GDIs because the victim drug may have multiple metabolic pathways and the perpetrator drug may affect multiple enzymes or transporters. Consequently, it is of great interest to both the pharmaceutical industry and regulatory agencies to determine if DDI studies can be leveraged to inform GDIs or vice versa for dose adjustment and labeling. The objective of this study was to investigate under what circumstances DDIs can be used to predict GDIs for prototypical CYP2C9, CYP2C19, and CYP2D6 substrates. We investigated model substrates for CYP2D6 (metoprolol, dextromethorphan, atomoxetine, and vortioxetine), CYP2C9 (warfarin, flurbiprofen, and celecoxib), and CYP2C19 (omeprazole and clopidogrel). Data on drug exposure for poor metabolizers (GDI) and for DDIs mediated by strong/moderate inhibitors in extensive metabolizers were collected. The impact of DDIs and GDIs on drug exposure was compared using: (1) a descriptive and (2) a physiologically based pharmacokinetic convergence analysis. Results from both approaches indicate that information on DDIs can be used to reliably predict GDIs for CYP2D6 substrates. The situation is more complex for CYP2C9 and CYP2C19 substrates because dose of the inhibitor (CYP2C9) and potency of the inhibitor (CYP2C19) impact the extent to which perpetrator drugs phenotypically convert extensive metabolizers to poor(er) metabolizers.
Topics: Area Under Curve; Computer Simulation; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochromes; Drug Interactions; Enzyme Inhibitors; Humans; Pharmacogenetics; Pharmacokinetics; Substrate Specificity
PubMed: 27040602
DOI: 10.1002/jcph.743