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Drug Metabolism Reviews Aug 2018Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role... (Review)
Review
Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.
Topics: Animals; Gastrointestinal Microbiome; Humans; Pharmacokinetics
PubMed: 30227749
DOI: 10.1080/03602532.2018.1497647 -
Current Drug Discovery Technologies Sep 2010The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of... (Review)
Review
The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of critical blood and biliary components. A number of liver-derived in vitro systems, such as slices, primary and immortalized hepatocytes, microsomes and S9 fractions are used to assess the metabolism and potential toxicity of new chemical entities. Over the past decade, primary hepatocytes have become a standard in vitro tool to evaluate hepatic drug metabolism, cytochrome P450 (P450) induction, and drug interactions affecting hepatic metabolism. While earlier, hepatocytes were used in suspension for metabolic stability evaluations, more recent studies have demonstrated the added value of using these over longer terms in primary culture. Primary hepatocyte cultures are particularly useful in the evaluation of low turn-over compounds. Hepatic transporter studies are recommended for drug candidates that are predominantly eliminated through the bile. An appropriate strategy is to use primary hepatocytes to assess uptake, followed by singly transfected cell lines to identify the specific transporter(s) involved. Primary hepatocytes can also be used to assess biliary clearance to enable improved hepatic clearance predictions. Newer technologies such as siRNA can be used to knock out specific transporters for more predictive evaluations of potential clinically-based drug-drug interactions. In vitro safety (toxicology) studies have historically been conducted using cell lines. There is increasing evidence that co-cultures of primary hepatocytes and Kupffer cells would be more predictive of the in vivo outcome, as this system provides the complete complement of drug metabolizing enzymes, transcription factors and cytokines necessary to get a more in vivo-like toxicological response. In this review, we will discuss standard and novel in vitro approaches for using primary hepatocytes to extrapolate clinical hepatic metabolism, transport and toxicity.
Topics: Animals; Biological Transport; Cytochrome P-450 Enzyme System; Drug Discovery; Drug Interactions; Hepatocytes; Humans; Liver; Metabolic Clearance Rate; Metabolic Networks and Pathways; Pharmaceutical Preparations
PubMed: 20843293
DOI: 10.2174/157016310793180576 -
Expert Opinion on Drug Metabolism &... Feb 2011It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes... (Review)
Review
INTRODUCTION
It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes have started to emerge only recently.
AREAS COVERED
This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock in xenobiotic metabolism at the transcriptional and post-transcriptional levels in the liver and intestine, and the different ways of elimination of these metabolized drugs via biliary and urine excretions. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver; however, the role of this timing system in the excretion of metabolized drugs and the importance of the kidney in this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion.
EXPERT OPINION
Chronopharmacology is used to analyze the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.
Topics: Animals; Bile; Biliary Tract; Circadian Clocks; Circadian Rhythm; Gene Expression Regulation; Humans; Inactivation, Metabolic; Kidney; Liver; Mammals; Pharmaceutical Preparations; Time Factors
PubMed: 21192771
DOI: 10.1517/17425255.2011.544251 -
Journal of Natural Products Jan 1983Drugs and other chemicals that do not occur in mammalian systems are metabolized by a wide variety of enzymes. Reactions catalyzed by these enzymes have been classified...
Drugs and other chemicals that do not occur in mammalian systems are metabolized by a wide variety of enzymes. Reactions catalyzed by these enzymes have been classified into two general phases. Phase I reactions include oxidations, reductions, and hydrolyses, whereas Phase II reactions are broadly defined as conjugation reactions and include glucuronidation, sulfation, acylation, methylation, and conjugation with glutathione. The mechanisms of these biotransformations are outlined to demonstrate how both non-toxic and toxic metabolites are produced. The mammalian metabolism of acetaminophen, a widely used mild analgesic, and R-(+)-pulegone, the major constituent terpene of pennyroyal oil, will be discussed to illustrate specific features of mammalian drug metabolism.
Topics: Abortifacient Agents; Acetaminophen; Acylation; Animals; Cyclohexanones; Humans; Hydrolysis; Inactivation, Metabolic; Mammals; Methylation; Mice; Mice, Inbred BALB C; Oils, Volatile; Oxidation-Reduction; Pharmaceutical Preparations; Terpenes
PubMed: 6854339
DOI: 10.1021/np50025a005 -
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 -
Chemico-biological Interactions Apr 2009Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic...
Drug metabolism can be a key determinant of drug toxicity. A nontoxic parent drug may be biotransformed by drug metabolizing enzymes to toxic metabolites (metabolic activation). Conversely, a toxic drug may be biotransformed to nontoxic metabolites (detoxification). The approaches to evaluate metabolism-based drug toxicity include the identification of toxic metabolites and the evaluation of toxicity in metabolically competent and metabolically compromised systems. A clear understanding of the role of drug metabolism in toxicity can aid the identification of risk factors that may potentiate drug toxicity, and may provide key information for the development of safe drugs.
Topics: Animals; Biotransformation; Drug Design; Drug Evaluation, Preclinical; Humans; Species Specificity; Toxicity Tests
PubMed: 19070611
DOI: 10.1016/j.cbi.2008.11.013 -
Expert Opinion on Drug Metabolism &... Jan 2009Metabolism is one of the key parameters to be investigated and optimized in drug discovery projects. Metabolically unstable compounds or potential inhibitors of... (Review)
Review
BACKGROUND
Metabolism is one of the key parameters to be investigated and optimized in drug discovery projects. Metabolically unstable compounds or potential inhibitors of important enzymes should be detected as early as possible. As more compounds are synthesized than can be investigated experimentally, powerful computational methods are needed.
OBJECTIVE
We give an overview of state-of-the-art in-silico methods to predict experimental metabolic endpoints with a focus on the applicability in pharmaceutical industry. A macroscopic as well as a microscopic view of the metabolic fate and the interaction with metabolizing enzymes are given.
METHODS
Ligand-, protein- and rule-based approaches are presented.
CONCLUSION
Although considerable progress has been made, the results of the calculations still need careful inspection. The domain of applicability of the models as well as methodological limitations have to be taken into account.
Topics: Biotransformation; Computational Biology; Databases, Factual; Enzyme Induction; Enzymes; Humans; Models, Molecular; Pharmaceutical Preparations; Protein Binding; Quantitative Structure-Activity Relationship
PubMed: 19236226
DOI: 10.1517/17425250802568009 -
Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.International Journal of Molecular... Sep 2022Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically... (Review)
Review
Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
Topics: Glycolysis; Hexokinase; Humans; Neoplasms; Phosphofructokinase-1; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Pyruvates; Tumor Microenvironment
PubMed: 36077431
DOI: 10.3390/ijms231710037 -
Drug Discovery Today Oct 2010In recent decades, our knowledge of the genetics and functional genomics of drug-metabolizing enzymes has increased and a wealth of data on drug-related 'omics' has... (Review)
Review
In recent decades, our knowledge of the genetics and functional genomics of drug-metabolizing enzymes has increased and a wealth of data on drug-related 'omics' has become available. Despite the availability of large amounts of biological information on xenobiotic biotransformation, the number of available biotransformation pathway maps that can easily be used for visualization of multiple omics data is limited. Here, we created integrated biotransformation pathway maps suitable for multiple omics analysis using PathVisio. The ease of visualizing data on these maps was demonstrated by using published microarray data from human hepatocyte-like cell models, exemplifying - where a sufficient capacity for metabolizing chemicals is a prerequisite for a suited model - how the biotransformation pathway maps can be used for model selection.
Topics: Biotransformation; Databases, Factual; Humans; Inactivation, Metabolic; Liver; Models, Biological; Pharmaceutical Preparations; Software
PubMed: 20708095
DOI: 10.1016/j.drudis.2010.08.002