-
International Journal of Molecular... Jan 2021The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in... (Review)
Review
The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.
Topics: ATP-Binding Cassette Transporters; Alleles; Animals; Biological Availability; Biological Transport; Biomarkers; Gastrointestinal Absorption; Gastrointestinal Tract; Gene Frequency; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Microsomes; Polymorphism, Single Nucleotide; Race Factors
PubMed: 33494365
DOI: 10.3390/ijms22031038 -
Methods in Molecular Biology (Clifton,... 2021The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their...
The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their crystallographic protein structures. Fortunately, despite low sequence similarity between different families of drug-metabolizing CYPs, there exists a high degree of structural homology within the superfamily. This similarity in the protein fold allows for a direct comparison of the structural features of CYPs that contribute toward differences in substrate binding, heterotropic and homotropic cooperativity, and genetic variability in drug metabolism. In this chapter, we first provide an overview of the nomenclature and the role of structural features that are common in all CYPs. We then apply these definitions to understand the different substrate specificities and functions in the CYP3A, CYP2C, and CYP2D families of enzymes.
Topics: Crystallography, X-Ray; Cytochrome P-450 Enzyme System; Genetic Variation; Humans; Inactivation, Metabolic; Kinetics; Models, Molecular; Protein Folding; Protein Structure, Secondary; Substrate Specificity
PubMed: 34272695
DOI: 10.1007/978-1-0716-1554-6_7 -
Chemico-biological Interactions May 20207H-Dibenzo[c,g]carbazole (DBC), a local and systemic carcinogen in animal studies, is a common environmental pollutant. It generally co-occurs in a variety of organic... (Review)
Review
7H-Dibenzo[c,g]carbazole (DBC), a local and systemic carcinogen in animal studies, is a common environmental pollutant. It generally co-occurs in a variety of organic complex mixtures derived from incomplete combustion of organic matter. Despite high lipophilicity, DBC is more water-soluble and faster metabolized than the homocyclic aromatics. Moreover, greater polarity, high bioaccumulation potential, and persistence in the environment may imply DBC's higher biological significance and impact on human health, even at lower concentrations. The biotransformation pathways of DBC are incompletely known and the ultimate carcinogenic metabolite(s) are not clearly identified as yet. Structure-biological studies suggest two ways of activation: at the ring carbon atoms and at the pyrrole nitrogen. It is supposed that the particular pathway of biotransformation might be connected with the tissue/organ specificity of DBC. Cytochrome P450 (CYP) family of enzymes plays a pivotal role in the metabolism of DBC; though, the one-electron activation and the aldo-keto reductase-catalyzed oxidation are also involved in metabolic activation. Additionally, DBC can be photoactivated even at physiologically relevant doses of UVA light due to the extended aromatic ring system resulting in strong genotoxicity and oxidative stress. The goal of this review is to summarize current knowledge on mechanisms of DBC activation and possible implications for toxicity, genotoxicity, and carcinogenicity.
Topics: Animals; Carbazoles; Carcinogenesis; Humans; Light; Metabolic Networks and Pathways; Oxidation-Reduction; Structure-Activity Relationship
PubMed: 32246921
DOI: 10.1016/j.cbi.2020.109077 -
Drug Metabolism and Disposition: the... Apr 2023Detailed assessment of the fate of drugs in nonclinical test species and humans is essential to ensure the safety and efficacy of medicines in patients. In this context,... (Review)
Review
Detailed assessment of the fate of drugs in nonclinical test species and humans is essential to ensure the safety and efficacy of medicines in patients. In this context, biotransformation of drugs and drug candidates has been an area of keen interest over many decades in the pharmaceutical industry as well as academia. Although many of the enzymes and biotransformation pathways involved in the metabolism of xenobiotics and more specifically drugs have been well characterized, each drug molecule is unique and constitutes specific challenges for the biotransformation scientist. In this mini-review written for the special issue on the occasion of the 50th Anniversary celebration of and to celebrate contributions of F. Peter Guengerich, one of the pioneers of the drug metabolism field, recently reported "unusual" biotransformation reactions are presented. Scientific and technological advances in the "toolbox" of the biotransformation scientists are summarized. As the pharmaceutical industry continues to explore therapeutic modalities different from the traditional small molecule drugs, the new challenges confronting the biotransformation scientist as well as future opportunities are discussed. SIGNIFICANCE STATEMENT: For the biotransformation scientists, it is essential to share and be aware of unexpected biotransformation reactions so that they can increase their confidence in predicting metabolites of drugs in humans to ensure the safety and efficacy of these metabolites before the medicines reach large numbers of patients. The purpose of this review is to highlight recent observations of "unusual" metabolites so that the scientists working in the area of drug metabolism can strengthen their readiness in expecting the unexpected.
Topics: Humans; Biotransformation; Inactivation, Metabolic; Xenobiotics; Drug Industry; Pharmaceutical Preparations
PubMed: 36653118
DOI: 10.1124/dmd.121.000744 -
European Journal of Cancer (Oxford,... Feb 2023Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour... (Review)
Review
Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.
Topics: Humans; Neoplasms; Energy Metabolism; Glycolysis; Mutation
PubMed: 36527974
DOI: 10.1016/j.ejca.2022.11.025 -
Current Drug Metabolism 2021Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients.
BACKGROUND
Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients.
OBJECTIVE
HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters in vitro were investigated to inform on the potential for drug-drug interactions (DDIs).
METHODS
A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment.
RESULTS
Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration- dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp.
CONCLUSION
The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Acetates; Adult; Animals; Antiviral Agents; Biotransformation; Cytochrome P-450 CYP3A; Cytomegalovirus; Cytomegalovirus Infections; Drug Elimination Routes; Drug Interactions; Glucuronosyltransferase; Healthy Volunteers; Hematopoietic Stem Cell Transplantation; Humans; Male; Medication Therapy Management; Neoplasm Proteins; Organic Anion Transporters; Quinazolines; Rats; Tissue Distribution
PubMed: 33622223
DOI: 10.2174/1389200222666210223112826 -
Drug Metabolism Reviews Feb 2020There are more than 1000 species of microbes reside in the human gut, umbering∼10 microbes. As the invisible organ of human beings, gut microbiota can usually... (Review)
Review
There are more than 1000 species of microbes reside in the human gut, umbering∼10 microbes. As the invisible organ of human beings, gut microbiota can usually participate in drug metabolism by producing specific enzymes, such as reductase and hydrolytic enzyme, thus affecting the efficacy, toxicity, and bioavailability of drugs. At least 30 commercially available drugs have been shown to be substrates of gut microbes-derived enzymes, and an increasing number of drugs may have the potential to contact with the distal gut with the help of improved release systems or poor solubility/permeability, more drugs are expected to be found to be metabolized through the gut flora. By collecting examples of intestinal flora participating in the metabolism of synthetic drugs and traditional Chinese medicine components, this article provides a comprehensive reference for future researchers to study drug metabolism by intestinal flora. Noticeably, the composition and quantity of intestinal flora varies among individuals, and can be affected by some drug administration (such as antibiotics) or environmental changes (acute plateau hypoxia). This seems to suggest that intestinal flora could have the potential to be a new drug target to affect the efficacy of drugs which can be metabolized by Intestinal flora. Accordingly, understanding the impact of intestinal flora on drug metabolism and clarifying the drug transformation process is of great significance for guiding rational clinical use, individualized use, toxicological evaluation, and promoting drug discovery and development.
Topics: Animals; Drugs, Chinese Herbal; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 32116054
DOI: 10.1080/03602532.2020.1718691 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Feb 2021The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required... (Review)
Review
The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.
Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Glutamine; Glycolysis; Humans; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment
PubMed: 34117847
DOI: 10.3724/zdxbyxb-2021-0040 -
Biochemical Pharmacology May 2023More and more studies highlight the complex metabolic characteristics and plasticity of cancer cells. To address these specificities and explore the associated... (Review)
Review
More and more studies highlight the complex metabolic characteristics and plasticity of cancer cells. To address these specificities and explore the associated vulnerabilities, new metabolism-targeting therapeutic strategies are being developed. It is more and more accepted that cancer cells do not produce their energy only from aerobic glycolysis, as some subtypes strongly rely on mitochondrial respiration (OXPHOS). This review focuses on classical and promising OXPHOS inhibitors (OXPHOSi), unravelling their interest and modes of actions in cancer, particularly in combination with other strategies. Indeed, in monotherapy, OXPHOSi display limited efficiency as they mostly trigger cell death in cancer cell subtypes that strongly depend on mitochondrial respiration and are not able to shift to other metabolic pathways to produce energy. Nevertheless, they remain very interesting in combination with conventional therapeutic strategies such as chemotherapy and radiotherapy, increasing their anti-tumoral actions. In addition, OXPHOSi can be included in even more innovative strategies such as combinations with other metabolic drugs or immunotherapies.
Topics: Humans; Energy Metabolism; Neoplasms; Antineoplastic Agents; Mitochondria; Metabolic Networks and Pathways; Oxidative Phosphorylation; Glycolysis
PubMed: 37019188
DOI: 10.1016/j.bcp.2023.115531