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Drug Metabolism and Personalized Therapy Jun 2015Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II... (Review)
Review
Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 (CYP) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.
Topics: Adult; Aged; Catechol O-Methyltransferase; Cytochrome P-450 Enzyme System; Genotype; Glucuronosyltransferase; Glutathione Transferase; Humans; Italy; Methyltransferases; Middle Aged; N-Terminal Acetyltransferases; Pharmaceutical Preparations; Polymorphism, Genetic; Sulfotransferases
PubMed: 25527811
DOI: 10.1515/dmdi-2014-0028 -
Drug Metabolism Reviews May 2019In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to... (Review)
Review
In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to evolve, thus, requiring ADME scientists to be knowledgeable of and engage with diverse aspects of drug assessment: from pharmacology to toxicology, and from modeling to models and finally models. Progress in this field requires deliberate exposure to different aspects of ADME; however, this task can seem daunting in the current age of mass information. We hope this review provides a focused and brief summary of a wide array of critical advances over the past year and explains the relevance of this research ( Table 1 ). We divided the articles into categories of (1) drug optimization, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation. This annual review is the fourth of its kind (Baillie et al. 2016 ; Khojasteh et al. 2017 , 2018 ). We have followed the same format we used in previous years in terms of the selection of articles and the authoring of each section. This effort in itself also continues to evolve. I am pleased that Rietjens, Miller, and Mitra have again contributed to this annual review. We would like to welcome Namandjé N. Bumpus, James P. Driscoll, and Donglu Zhang as authors for this year's issue. We strive to maintain a balance of authors from academic and industry settings. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. Cyrus Khojasteh, on behalf of the authors.
Topics: Activation, Metabolic; Animals; Biotransformation; Humans
PubMed: 31170851
DOI: 10.1080/03602532.2019.1615937 -
Drug Metabolism and Disposition: the... Dec 2023Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades,...
Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo extrapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of will summarize the latest progress in in silico, in vitro, and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposition in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps that present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight opportunities for multistakeholder collaboration to advance our collective understanding of this rapidly emerging area. SIGNIFICANCE STATEMENT: This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of drug-metabolizing enzymes and transporters (DMETs) in drug disposition in specific populations. With this commentary for the special issue in , the authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.
Topics: Pregnancy; Female; Humans; Child; Membrane Transport Proteins; Liver Diseases; Drug Interactions; Inflammation; Metabolic Clearance Rate
PubMed: 37775331
DOI: 10.1124/dmd.123.001453 -
Drug Metabolism and Disposition: the... Dec 2014The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in... (Review)
Review
The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition.
Topics: Drug Interactions; Humans; Inactivation, Metabolic; Pharmaceutical Preparations; United States; United States Food and Drug Administration
PubMed: 25271211
DOI: 10.1124/dmd.114.060392 -
Drug Metabolism Reviews Aug 2018With the inclusion of mesentery, the total number of human organs has recently increased by one. The mesentery was formerly construed to be a complex, discontinuous... (Review)
Review
With the inclusion of mesentery, the total number of human organs has recently increased by one. The mesentery was formerly construed to be a complex, discontinuous anatomical structure simply serving as a support for organs in abdominal cavity. However, recent research has established the mesentery to be a far more simple and unfragmented organ. Newly emerging information on the mesentery has challenged some older pathophysiological concepts. This review briefly discusses the anatomy of the mesentery, historical perspective on the mesentery, embryology, drug metabolizing enzymes and transporters of the mesentery, and the mesentery's role in diseases. The possible impact of the mesentery on absorption, distribution, metabolism, and excretion (ADME) is also discussed.
Topics: Animals; Biological Transport, Active; Humans; Mesentery; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 30009643
DOI: 10.1080/03602532.2018.1484756 -
Biomolecules Aug 2021Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely... (Review)
Review
Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR's regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.
Topics: Acetylation; Antineoplastic Agents; Biotransformation; Gene Expression; Humans; Inactivation, Metabolic; Neoplasms; Phosphorylation; Polymorphism, Single Nucleotide; Precision Medicine; Pregnane X Receptor; Protein Domains; Protein Processing, Post-Translational; Sumoylation; Treatment Outcome; Ubiquitination
PubMed: 34439808
DOI: 10.3390/biom11081142 -
Drug Metabolism Reviews May 2021As lead optimization efforts have successfully reduced metabolic liabilities due to cytochrome P450 (CYP)-mediated metabolism, there has been an increase in the...
As lead optimization efforts have successfully reduced metabolic liabilities due to cytochrome P450 (CYP)-mediated metabolism, there has been an increase in the frequency of involvement of non-CYP enzymes in the metabolism of investigational compounds. Although there have been numerous notable advancements in the characterization of non-CYP enzymes with respect to their localization, reaction mechanisms, species differences and identification of typical substrates, accurate prediction of non-CYP-mediated clearance, with a particular emphasis with the difficulties in accounting for any extrahepatic contributions, remains a challenge. The current manuscript comprehensively summarizes the recent advancements in the prediction of drug metabolism and the to extrapolation of clearance for substrates of non-CYP drug metabolizing enzymes.
Topics: Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Microsomes, Liver
PubMed: 33941024
DOI: 10.1080/03602532.2021.1923728