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Current Opinion in Gastroenterology May 2015It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests... (Review)
Review
PURPOSE OF REVIEW
It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high-affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways.
RECENT FINDINGS
We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting.
SUMMARY
It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy.
Topics: Cholates; Health Services Needs and Demand; Hepatocytes; Humans; Liver; Liver Diseases; Liver Function Tests; Metabolic Clearance Rate; Predictive Value of Tests; Severity of Illness Index
PubMed: 25714706
DOI: 10.1097/MOG.0000000000000167 -
Current Neuropharmacology 2019Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a... (Review)
Review
BACKGROUND
Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.
METHODS
CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.
RESULTS
The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.
CONCLUSION
Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.
Topics: Adult; Age Factors; Anticonvulsants; Biosynthetic Pathways; Child; Cytochrome P-450 CYP2C9; Epilepsy; Genotype; Humans; Phenotype; Polymorphism, Genetic; Valproic Acid
PubMed: 29119932
DOI: 10.2174/1570159X15666171109143654 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183 -
Biochimica Et Biophysica Acta Sep 2016The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of... (Review)
Review
The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. 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; Constitutive Androstane Receptor; Energy Metabolism; Gene Expression Regulation; Heat-Shock Proteins; Humans; Inactivation, Metabolic; Intercellular Signaling Peptides and Proteins; Liver; Mitogen-Activated Protein Kinases; Phosphorylation; Pregnane X Receptor; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Xenobiotics
PubMed: 26877237
DOI: 10.1016/j.bbagrm.2016.02.006 -
European Journal of Pharmaceutical... Apr 2023A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized...
A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized by high inter- and intraindividual differences, but their impact on drug distribution and efficacy remains incompletely understood. This research gap is pressing, as, e.g., inflammatory disorders of the colon are on the rise globally. In an effort to help close this gap, we provide considerations on determining colonic epithelial and microbial cellular parameters, and their impact on drug bioavailability. First, we cover the major cell types found in vivo within the epithelium and microbiota, and discuss how they can be modeled in vitro. We then draw attention to their structural similarities and differences with regard to determinants of drug distribution. Once a drug is solubilized in the luminal fluids, there are two main classes of such determinants: 1) binding processes, and 2) transporters and drug-metabolizing enzymes. Binding lowers the unbound intracellular fraction (f), which will, in turn, limit the amount of drug available for transport to desired sites. Transporters and drug metabolizing enzymes are ADME proteins impacting intracellular accumulation (Kp). Across cell types, we point out which processes are likely particularly impactful. Together, f and Kp can be used to describe intracellular bioavailability (F), which is a measure of local drug distribution, with consequences for efficacy. Determining these cellular parameters will be beneficial in understanding colonic drug distribution and will advance the field of drug delivery.
Topics: Epithelial Cells; Colon; Epithelium; Biological Availability; Pharmaceutical Preparations; Membrane Transport Proteins
PubMed: 36690119
DOI: 10.1016/j.ejps.2023.106389 -
Scientific Reports Jan 2021Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet...
Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet the cellular and metabolic processes within the biological component of this system are still elusive. Here we dissect the biohybrid composed of the anaerobic acetogenic bacterium Moorella thermoacetica and cadmium sulphide nanoparticles (CdS) in terms of physiology, metabolism, enzymatics and transcriptomic profiling. Our analyses show that while the organism does not grow on L-cysteine, it is metabolized to acetate in the biohybrid system and this metabolism is independent of CdS or light. CdS cells have higher metabolic activity, despite an inhibitory effect of Cd on key enzymes, because of an intracellular storage compound linked to arginine metabolism. We identify different routes how cysteine and its oxidized form can be innately metabolized by the model acetogen and what intracellular mechanisms are triggered by cysteine, cadmium or blue light.
Topics: Acetates; Biological Transport; Cadmium; Carbon; Carbon Isotopes; Complex Mixtures; Cysteine; Energy Metabolism; Gene Expression Regulation, Bacterial; Light; Magnetic Resonance Spectroscopy; Moorella; Oxidation-Reduction; Transcriptome
PubMed: 33495538
DOI: 10.1038/s41598-021-81103-z -
Physiology & Behavior Dec 2015Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic... (Review)
Review
Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic effects. However, data from several epidemiological studies have found that consumption of NNSs, mainly in diet sodas, is associated with increased risk to develop obesity, metabolic syndrome, and type 2 diabetes. The main purpose of this article is to review recent scientific evidence supporting potential mechanisms that explain how "metabolically inactive" NNSs, which have few, if any, calories, might promote metabolic dysregulation. Three potential mechanisms, which are not mutually exclusive, are presented: 1) NNSs interfere with learned responses that contribute to control glucose and energy homeostasis, 2) NNSs interfere with gut microbiota and induce glucose intolerance, and 3) NNSs interact with sweet-taste receptors expressed throughout the digestive system that play a role in glucose absorption and trigger insulin secretion. In addition, recent findings from our laboratory showing an association between individual taste sensitivity to detect sucralose and sucralose's acute effects on metabolic response to an oral glucose load are reported. Taken as a whole, data support the notion that NNSs have metabolic effects. More research is needed to elucidate the mechanisms by which NNSs may drive metabolic dysregulation and better understand potential effects of these commonly used food additives.
Topics: Animals; Energy Metabolism; Enteroendocrine Cells; Humans; Non-Nutritive Sweeteners
PubMed: 26095119
DOI: 10.1016/j.physbeh.2015.06.024 -
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 -
Drug Metabolism and Disposition: the... Aug 2015The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014...
The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic β-cell dysfunction and may have a role in how uremic toxins enter pancreatic β-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
Topics: Animals; Biological Transport; Biological Transport, Active; Drug Delivery Systems; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 25986849
DOI: 10.1124/dmd.115.064576