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Tremmel R, Hübschmann D, Schaeffeler E, Pirmann S, Fröhling S, Schwab M. Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes. Pharmacol Rev 2025; 77:100014. [PMID: 39952686 DOI: 10.1124/pharmrev.124.001049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 10/02/2024] [Accepted: 10/04/2024] [Indexed: 01/22/2025] Open
Abstract
Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or are in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, for example, somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for >5 decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information, which derives from both the tumor and the germline genome, and taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to integrate PGx data in cancer therapy with a special meaning for interdisciplinary molecular tumor boards, in which cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. SIGNIFICANCE STATEMENT: The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, the full potential of targeted therapy remains untapped owing to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.
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Affiliation(s)
- Roman Tremmel
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany
| | - Daniel Hübschmann
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between the German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany; Innovation and Service Unit for Bioinformatics and Precision Medicine, DKFZ, Heidelberg, Germany; Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tuebingen, Tuebingen, Germany
| | - Sebastian Pirmann
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between the German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Fröhling
- German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Heidelberg, Germany; Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tuebingen, Tuebingen, Germany; Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany; DKTK, DKFZ, Partner Site Tuebingen, Tuebingen, Germany; NCT SouthWest, a partnership between DKFZ and University Hospital Tuebingen, Tuebingen, Germany.
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Guengerich FP. Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism. Pharmacol Rev 2024; 76:1104-1132. [PMID: 39054072 PMCID: PMC11549934 DOI: 10.1124/pharmrev.124.001173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/28/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024] Open
Abstract
Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"]. SIGNIFICANCE STATEMENT: Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.
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Affiliation(s)
- F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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3
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Becker D, Bharatam PV, Gohlke H. Molecular Mechanisms Underlying Single Nucleotide Polymorphism-Induced Reactivity Decrease in CYP2D6. J Chem Inf Model 2024; 64:6026-6040. [PMID: 38994927 DOI: 10.1021/acs.jcim.4c00276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects, and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing cytochrome P450 enzymes.
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Affiliation(s)
- Daniel Becker
- Mathematisch-Naturwissenschaftliche Fakultät, Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Mohali, Punjab 160 062, India
| | - Holger Gohlke
- Mathematisch-Naturwissenschaftliche Fakultät, Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
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4
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Ingelman-Sundberg M, Nebert DW, Lauschke VM. Emerging trends in pharmacogenomics: from common variant associations toward comprehensive genomic profiling. Hum Genomics 2023; 17:105. [PMID: 37996916 PMCID: PMC10668450 DOI: 10.1186/s40246-023-00554-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023] Open
Affiliation(s)
| | - Daniel W Nebert
- Department of Environmental and Public Health Sciences, Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Pediatrics and Molecular & Developmental Biology, Cincinnati Children's Research Center, Cincinnati, OH, 45229, USA
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden.
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
- University of Tübingen, Tübingen, Germany.
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5
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Papachristos A, Patel J, Vasileiou M, Patrinos GP. Dose Optimization in Oncology Drug Development: The Emerging Role of Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics. Cancers (Basel) 2023; 15:3233. [PMID: 37370844 DOI: 10.3390/cancers15123233] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Drugs' safety and effectiveness are evaluated in randomized, dose-ranging trials in most therapeutic areas. However, this is only sometimes feasible in oncology, and dose-ranging studies are mainly limited to Phase 1 clinical trials. Moreover, although new treatment modalities (e.g., small molecule targeted therapies, biologics, and antibody-drug conjugates) present different characteristics compared to cytotoxic agents (e.g., target saturation limits, wider therapeutic index, fewer off-target side effects), in most cases, the design of Phase 1 studies and the dose selection is still based on the Maximum Tolerated Dose (MTD) approach used for the development of cytotoxic agents. Therefore, the dose was not optimized in some cases and was modified post-marketing (e.g., ceritinib, dasatinib, niraparib, ponatinib, cabazitaxel, and gemtuzumab-ozogamicin). The FDA recognized the drawbacks of this approach and, in 2021, launched Project Optimus, which provides the framework and guidance for dose optimization during the clinical development stages of anticancer agents. Since dose optimization is crucial in clinical development, especially of targeted therapies, it is necessary to identify the role of pharmacological tools such as pharmacogenomics, therapeutic drug monitoring, and pharmacodynamics, which could be integrated into all phases of drug development and support dose optimization, as well as the chances of positive clinical outcomes.
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Affiliation(s)
| | - Jai Patel
- Department of Cancer Pharmacology and Pharmacogenomics, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, USA
| | - Maria Vasileiou
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 16121 Athens, Greece
| | - George P Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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6
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Guengerich FP. Drug Metabolism: A Half-Century Plus of Progress, Continued Needs, and New Opportunities. Drug Metab Dispos 2023; 51:99-104. [PMID: 35868640 PMCID: PMC11024512 DOI: 10.1124/dmd.121.000739] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 06/13/2022] [Accepted: 06/28/2022] [Indexed: 01/19/2023] Open
Abstract
The systematic study of drug metabolism began in the 19th Century, but most of what we know now has been learned in the last 50 years. Drug metabolism continues to play a critical role in pharmaceutical development and clinical practice, as well as contributing to toxicology, chemical carcinogenesis, endocrinology, and drug abuse. The importance of the field will continue, but its nature will continue to develop with changes in analytical chemistry, structural biology, and artificial intelligence. Challenges and opportunities include toxicology, defining roles of genetic variations, and application to clinical issues. Although the focus of this Minireview is cytochrome P450, the same principles apply to other enzymes and transporters involved in drug metabolism. SIGNIFICANCE STATEMENT: Progress in the field of drug metabolism over the past 50 years has helped make the pharmaceutical enterprise what it is today. Drug metabolism will continue to be important. Challenges and opportunities for the future are discussed.
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Affiliation(s)
- F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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7
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Bai H, Zhang X, Bush WS. Pharmacogenomic and Statistical Analysis. Methods Mol Biol 2023; 2629:305-330. [PMID: 36929083 DOI: 10.1007/978-1-0716-2986-4_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical considerations. Genetic variants involved in the processing of exogenous compounds exhibit great diversity and complexity, and the phenotypes studied in pharmacogenomics are also more complex than typical genetic studies. In this chapter, we review basic concepts in pharmacogenomic study designs, data generation techniques, statistical analysis approaches, and commonly used methods and briefly discuss the ultimate translation of findings to clinical care.
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Affiliation(s)
- Haimeng Bai
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Xueyi Zhang
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - William S Bush
- Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
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8
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Ko FS. The Simon’s two-stage design accounting for genetic heterogeneity. COMMUN STAT-THEOR M 2022. [DOI: 10.1080/03610926.2022.2148469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Feng-shou Ko
- KF Statistical Consulting Company, Kaohsiung, Taiwan R.O.C
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9
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Grzegorzewski J, Brandhorst J, König M. Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan. Front Pharmacol 2022; 13:1029073. [PMID: 36353484 PMCID: PMC9637881 DOI: 10.3389/fphar.2022.1029073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/23/2022] [Indexed: 11/24/2022] Open
Abstract
The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO + DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.
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Affiliation(s)
- Jan Grzegorzewski
- Institute for Theoretical Biology, Institute of Biology, Humboldt University, Berlin, Germany
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Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone. Pharmaceutics 2022; 14:pharmaceutics14081734. [PMID: 36015360 PMCID: PMC9414337 DOI: 10.3390/pharmaceutics14081734] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/12/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug–gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim®, using a total of 57 plasma concentration–time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound’s exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively.
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11
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Daly AK. Pharmacogenetics of the cytochromes P450: Selected pharmacological and toxicological aspects. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 95:49-72. [PMID: 35953163 DOI: 10.1016/bs.apha.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.
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Affiliation(s)
- Ann K Daly
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom.
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12
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Auwerx C, Sadler MC, Reymond A, Kutalik Z. From pharmacogenetics to pharmaco-omics: Milestones and future directions. HGG ADVANCES 2022; 3:100100. [PMID: 35373152 PMCID: PMC8971318 DOI: 10.1016/j.xhgg.2022.100100] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The origins of pharmacogenetics date back to the 1950s, when it was established that inter-individual differences in drug response are partially determined by genetic factors. Since then, pharmacogenetics has grown into its own field, motivated by the translation of identified gene-drug interactions into therapeutic applications. Despite numerous challenges ahead, our understanding of the human pharmacogenetic landscape has greatly improved thanks to the integration of tools originating from disciplines as diverse as biochemistry, molecular biology, statistics, and computer sciences. In this review, we discuss past, present, and future developments of pharmacogenetics methodology, focusing on three milestones: how early research established the genetic basis of drug responses, how technological progress made it possible to assess the full extent of pharmacological variants, and how multi-dimensional omics datasets can improve the identification, functional validation, and mechanistic understanding of the interplay between genes and drugs. We outline novel strategies to repurpose and integrate molecular and clinical data originating from biobanks to gain insights analogous to those obtained from randomized controlled trials. Emphasizing the importance of increased diversity, we envision future directions for the field that should pave the way to the clinical implementation of pharmacogenetics.
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Affiliation(s)
- Chiara Auwerx
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Marie C. Sadler
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Alexandre Reymond
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Zoltán Kutalik
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
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13
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Alali M, Ismail Al-khalil W, Rijjal S, Al-Salhi L, Saifo M, Youssef LA. Frequencies of CYP2D6 genetic polymorphisms in Arab populations. Hum Genomics 2022; 16:6. [PMID: 35123571 PMCID: PMC8817534 DOI: 10.1186/s40246-022-00378-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
CYP2D6 is a key drug-metabolizing enzyme implicated in the biotransformation of approximately 25% of currently prescribed drugs. Interindividual and interethnic differences in CYP2D6 enzymatic activity, and hence variability in substrate drug efficacy and safety, are attributed to a highly polymorphic corresponding gene. This study aims at reviewing the frequencies of the most clinically relevant CYP2D6 alleles in the Arabs countries. Articles published before May 2021 that reported CYP2D6 genotype and allelic frequencies in the Arab populations of the Middle East and North Africa (MENA) region were retrieved from PubMed and Google Scholar databases. This review included 15 original articles encompassing 2737 individuals from 11 countries of the 22 members of the League of Arab States. Active CYP2D6 gene duplications reached the highest frequencies of 28.3% and 10.4% in Algeria and Saudi Arabia, respectively, and lowest in Egypt (2.41%) and Palestine (4.9%). Frequencies of the loss-of-function allele CYP2D6*4 ranged from 3.5% in Saudi Arabia to 18.8% in Egypt. The disparity in frequencies of the reduced-function CYP2D6*10 allele was perceptible, with the highest frequency reported in Jordan (14.8%) and the lowest in neighboring Palestine (2%), and in Algeria (0%). The reduced-function allele CYP2D6*41 was more prevalent in the Arabian Peninsula countries; Saudi Arabia (18.4%) and the United Arab Emirates (15.2%), in comparison with the Northern Arab-Levantine Syria (9.7%) and Algeria (8.3%). Our study demonstrates heterogeneity of CYP2D6 alleles among Arab populations. The incongruities of the frequencies of alleles in neighboring countries with similar demographic composition emphasize the necessity for harmonizing criteria of genotype assignment and conducting comprehensive studies on larger MENA Arab populations to determine their CYP2D6 allelic makeup and improve therapeutic outcomes of CYP2D6- metabolized drugs.
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Affiliation(s)
- Mousa Alali
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
| | - Wouroud Ismail Al-khalil
- Program of Clinical and Hospital Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Mezzeh Autostrad, Damascus, Syrian Arab Republic
| | - Sara Rijjal
- Program of Clinical and Hospital Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Mezzeh Autostrad, Damascus, Syrian Arab Republic
| | - Lana Al-Salhi
- Program of Clinical and Hospital Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Mezzeh Autostrad, Damascus, Syrian Arab Republic
| | - Maher Saifo
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
| | - Lama A. Youssef
- Program of Clinical and Hospital Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Mezzeh Autostrad, Damascus, Syrian Arab Republic
- Faculty of Pharmacy, International University for Science and Technology (IUST), Ghabagheb, Daraa Syrian Arab Republic
- National Commission for Biotechnology (NCBT), Damascus, Syrian Arab Republic
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Neul C, Hofmann U, Schaeffeler E, Winter S, Klein K, Giacomini KM, Eichelbaum M, Schwab M, Nies AT. Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins. Br J Pharmacol 2021; 178:1459-1474. [PMID: 33434947 DOI: 10.1111/bph.15370] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 11/24/2020] [Accepted: 12/21/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND PURPOSE The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine. EXPERIMENTAL APPROACH OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1-, and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype. KEY RESULTS OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype. CONCLUSIONS AND IMPLICATIONS Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.
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Affiliation(s)
- Claudia Neul
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Ute Hofmann
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
| | - Stefan Winter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Kathrin Klein
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Kathleen M Giacomini
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.,Institute of Human Genetics, University of California, San Francisco, California, USA
| | - Michel Eichelbaum
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany
| | - Anne T Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tuebingen, Tuebingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
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15
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Caspar SM, Schneider T, Stoll P, Meienberg J, Matyas G. Potential of whole-genome sequencing-based pharmacogenetic profiling. Pharmacogenomics 2021; 22:177-190. [PMID: 33517770 DOI: 10.2217/pgs-2020-0155] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Pharmacogenetics represents a major driver of precision medicine, promising individualized drug selection and dosing. Traditionally, pharmacogenetic profiling has been performed using targeted genotyping that focuses on common/known variants. Recently, whole-genome sequencing (WGS) is emerging as a more comprehensive short-read next-generation sequencing approach, enabling both gene diagnostics and pharmacogenetic profiling, including rare/novel variants, in a single assay. Using the example of the pharmacogene CYP2D6, we demonstrate the potential of WGS-based pharmacogenetic profiling as well as emphasize the limitations of short-read next-generation sequencing. In the near future, we envision a shift toward long-read sequencing as the predominant method for gene diagnostics and pharmacogenetic profiling, providing unprecedented data quality and improving patient care.
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Affiliation(s)
- Sylvan Manuel Caspar
- Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland.,Department of Health Sciences & Technology, Laboratory of Translational Nutrition Biology, ETH Zurich, Schwerzenbach 8603, Switzerland
| | - Timo Schneider
- Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland
| | - Patricia Stoll
- Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland
| | - Janine Meienberg
- Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland
| | - Gabor Matyas
- Center for Cardiovascular Genetics & Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich 8952, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich 8057, Switzerland
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16
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Guengerich FP. A history of the roles of cytochrome P450 enzymes in the toxicity of drugs. Toxicol Res 2021; 37:1-23. [PMID: 32837681 PMCID: PMC7431904 DOI: 10.1007/s43188-020-00056-z] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 05/22/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.
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Affiliation(s)
- F. Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, 638B Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0146 USA
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17
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Carvalho Henriques B, Yang EH, Lapetina D, Carr MS, Yavorskyy V, Hague J, Aitchison KJ. How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing? Front Genet 2020; 11:491895. [PMID: 33363564 PMCID: PMC7753050 DOI: 10.3389/fgene.2020.491895] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/25/2020] [Indexed: 12/11/2022] Open
Abstract
Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug-drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.
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Affiliation(s)
| | - Esther H. Yang
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Diego Lapetina
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Michael S. Carr
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Vasyl Yavorskyy
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Joshua Hague
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Katherine J. Aitchison
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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18
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Visvikis-Siest S, Theodoridou D, Kontoe MS, Kumar S, Marschler M. Milestones in Personalized Medicine: From the Ancient Time to Nowadays-the Provocation of COVID-19. Front Genet 2020; 11:569175. [PMID: 33424917 PMCID: PMC7794000 DOI: 10.3389/fgene.2020.569175] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/26/2020] [Indexed: 12/15/2022] Open
Abstract
The first evidence of individual targeting medicine appeared in ancient times thousands of years ago. Various therapeutic approaches have been established since then. However, even nowadays, conventional therapies do not take into consideration individuals' idiosyncrasy and genetic make-up, failing thus to be effective in some cases. Over time, the necessity of a more precise and effective treatment resulted in the development of a scientific field currently known as “personalized medicine.” The numerous technological breakthroughs in this field have acknowledged personalized medicine as the next generation of diagnosis and treatment. Although personalized medicine has attracted a lot of attention the last years, there are still several obstacles hindering its application in clinical practice. These limitations have come to light recently, due to the COVID-19 pandemic. This review describes the “journey” of personalized medicine over time, emphasizing on important milestones achieved through time. Starting from the treatment of malaria, as a first more personalized therapeutic approach, it highlights the need of new diagnostic tools and therapeutic regimens based on individuals' genetic background. Furthermore, it aims at raising global awareness regarding the current limitations and the necessity of a personalized strategy to overpass healthcare problems and hence, the current crisis.
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Affiliation(s)
- Sophie Visvikis-Siest
- Université de Lorraine, IGE-PCV, Nancy, France.,The Santorini Conferences (SCs) Association, Nancy, France
| | - Danai Theodoridou
- Université de Lorraine, IGE-PCV, Nancy, France.,The Santorini Conferences (SCs) Association, Nancy, France
| | - Maria-Spyridoula Kontoe
- Université de Lorraine, IGE-PCV, Nancy, France.,The Santorini Conferences (SCs) Association, Nancy, France
| | - Satish Kumar
- Université de Lorraine, IGE-PCV, Nancy, France.,The Santorini Conferences (SCs) Association, Nancy, France
| | - Michael Marschler
- Université de Lorraine, IGE-PCV, Nancy, France.,The Santorini Conferences (SCs) Association, Nancy, France
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19
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Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes (Basel) 2020; 11:E1295. [PMID: 33143137 PMCID: PMC7692531 DOI: 10.3390/genes11111295] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/25/2020] [Accepted: 10/28/2020] [Indexed: 12/14/2022] Open
Abstract
Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.
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Affiliation(s)
- Christopher Taylor
- Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool L69 3BX, UK; (V.Y.); (M.P.); (R.M.T.)
- MC Diagnostics, St Asaph Business Park, Saint Asaph LL17 0LJ, UK; (I.C.); (P.M.)
| | - Ian Crosby
- MC Diagnostics, St Asaph Business Park, Saint Asaph LL17 0LJ, UK; (I.C.); (P.M.)
| | - Vincent Yip
- Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool L69 3BX, UK; (V.Y.); (M.P.); (R.M.T.)
| | - Peter Maguire
- MC Diagnostics, St Asaph Business Park, Saint Asaph LL17 0LJ, UK; (I.C.); (P.M.)
| | - Munir Pirmohamed
- Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool L69 3BX, UK; (V.Y.); (M.P.); (R.M.T.)
| | - Richard M. Turner
- Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool L69 3BX, UK; (V.Y.); (M.P.); (R.M.T.)
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20
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Nassar SF, Raddassi K, Ubhi B, Doktorski J, Abulaban A. Precision Medicine: Steps along the Road to Combat Human Cancer. Cells 2020; 9:E2056. [PMID: 32916938 PMCID: PMC7563722 DOI: 10.3390/cells9092056] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022] Open
Abstract
The diagnosis and treatment of diseases such as cancer is becoming more accurate and specialized with the advent of precision medicine techniques, research and treatments. Reaching down to the cellular and even sub-cellular level, diagnostic tests can pinpoint specific, individual information from each patient, and guide providers to a more accurate plan of treatment. With this advanced knowledge, researchers and providers can better gauge the effectiveness of drugs, radiation, and other therapies, which is bound to lead to a more accurate, if not more positive, prognosis. As precision medicine becomes more established, new techniques, equipment, materials and testing methods will be required. Herein, we will examine the recent innovations in assays, devices and software, along with next generation sequencing in genomics diagnostics which are in use or are being developed for personalized medicine. So as to avoid duplication and produce the fullest possible benefit, all involved must be strongly encouraged to collaborate, across national borders, public and private sectors, science, medicine and academia alike. In this paper we will offer recommendations for tools, research and development, along with ideas for implementation. We plan to begin with discussion of the lessons learned to date, and the current research on pharmacogenomics. Given the steady stream of advances in imaging mass spectrometry and nanoLC-MS/MS, and use of genomic, proteomic and metabolomics biomarkers to distinguish healthy tissue from diseased cells, there is great potential to utilize pharmacogenomics to tailor a drug or drugs to a particular cohort of patients. Such efforts very well may bring increased hope for small groups of non-responders and those who have demonstrated adverse reactions to current treatments.
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Affiliation(s)
- Samuel F. Nassar
- Department of Biology, Brandeis University, Waltham, MA 02453, USA
| | - Khadir Raddassi
- Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA;
| | | | | | - Ahmad Abulaban
- Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA;
- Department of Medicine, King Saud Bin-Abdulaziz University, King Abdulaziz Medical City-National Guard Health Affairs, Riyadh 11426, Saudi Arabia
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21
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Edris A, Vanoverschelde A, Bushaj P, Van Nieuwerburgh F, Lahousse L. Pharmacogenetics in clinical practice: current level of knowledge among Flemish physicians and pharmacists. THE PHARMACOGENOMICS JOURNAL 2020; 21:78-84. [PMID: 32848197 DOI: 10.1038/s41397-020-00180-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 06/17/2020] [Accepted: 08/12/2020] [Indexed: 12/27/2022]
Abstract
Over the past decade, pharmacogenetics (PGx) became an essential tool for personalized medicine although its clinical implementation is still limited. We aimed to assess the current level of knowledge, applications, and expectations of Flemish pharmacists and physicians towards PGx and determine the factors that influence healthcare professionals' knowledge of PGx, aiming to guide future implementation initiatives. A web-based cross-sectional survey was conducted from 8 March 2019 to 8 April 2019, targeting pharmacists, physicians, and trainees of both professions. Ten questions were used to assess the participants' knowledge about PGx. Multivariable linear regression was used to assess the association of profession, experience, practice setting, and prior education with the level of PGx knowledge. In total, 201 Flemish healthcare providers participated, including 100 pharmacists, 73 physicians, and 28 trainees. The majority (78%) of participants were unfamiliar with the basic principles of PGx and its application in clinical practice. The mean percentage of correct answers achieved for the knowledge assessment questions was 34%. Only 9% had counseled patients, while 8% assisted other healthcare professionals on PGx tests the past year. Participants' PGx knowledge was significantly affected by their profession, practice setting, and level of prior education independent of years of experience. These findings provide insight into factors affecting the knowledge of PGx and the current level of PGx implementation in Flemish clinical practice. This may form a basis for developing educational initiatives to enhance the clinical application of PGx in Flanders.
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Affiliation(s)
- Ahmed Edris
- Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium
| | - Anna Vanoverschelde
- Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium
| | - Pranvera Bushaj
- Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium
| | | | - Lies Lahousse
- Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium.
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22
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Lapetina DL, Yang EH, Henriques BC, Aitchison KJ. Pharmacogenomics and Psychopharmacology. SEMINARS IN CLINICAL PSYCHOPHARMACOLOGY 2020:151-202. [DOI: 10.1017/9781911623465.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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Monitoring of tricyclic antidepressant plasma levels and clinical response: a review of the literature. Part II. ACTA ACUST UNITED AC 2020. [DOI: 10.1017/s0767399x00002911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
SummaryPart II of this paper contains some general considerations on tricyclic antidepressant (TCA) monitoring. Long-term assessment of TCA plasma levels is advised by the few existent studies, although each of these focusses on different aspects. Cardiovascular and central nervous system toxicity is reviewed as well as pharmacokinetics and the importance of protein binding. Some consideration is also given to their use in elderly patients. The authors conclude that although available data support its usefulness in many situations, routine measurement of TCA levels is not warranted.
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24
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Tolledo EC, Miksys S, Gonzalez FJ, Tyndale RF. Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: Effects on activity and drug responses. Br J Pharmacol 2020; 177:701-712. [PMID: 31648367 PMCID: PMC7012948 DOI: 10.1111/bph.14884] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/16/2019] [Accepted: 09/13/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours. EXPERIMENTAL APPROACH Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied. KEY RESULTS Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg-1 intraperitoneal propranolol reduced dextrorphan formation in vivo and by liver microsomes in vitro. Serum haloperidol levels and catalepsy were increased. CONCLUSIONS AND IMPLICATIONS Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.
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Affiliation(s)
- Edgor Cole Tolledo
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology & Toxicology, Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
| | - Sharon Miksys
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology & Toxicology, Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Rachel F. Tyndale
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology & Toxicology, Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
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25
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Özdemir V, Arga KY, Aziz RK, Bayram M, Conley SN, Dandara C, Endrenyi L, Fisher E, Garvey CK, Hekim N, Kunej T, Şardaş S, Von Schomberg R, Yassin AS, Yılmaz G, Wang W. Digging Deeper into Precision/Personalized Medicine: Cracking the Sugar Code, the Third Alphabet of Life, and Sociomateriality of the Cell. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 24:62-80. [PMID: 32027574 DOI: 10.1089/omi.2019.0220] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Precision/personalized medicine is a hot topic in health care. Often presented with the motto "the right drug, for the right patient, at the right dose, and the right time," precision medicine is a theory for rational therapeutics as well as practice to individualize health interventions (e.g., drugs, food, vaccines, medical devices, and exercise programs) using biomarkers. Yet, an alien visitor to planet Earth reading the contemporary textbooks on diagnostics might think precision medicine requires only two biomolecules omnipresent in the literature: nucleic acids (e.g., DNA) and proteins, known as the first and second alphabet of biology, respectively. However, the precision/personalized medicine community has tended to underappreciate the third alphabet of life, the "sugar code" (i.e., the information stored in glycans, glycoproteins, and glycolipids). This article brings together experts in precision/personalized medicine science, pharmacoglycomics, emerging technology governance, cultural studies, contemporary art, and responsible innovation to critically comment on the sociomateriality of the three alphabets of life together. First, the current transformation of targeted therapies with personalized glycomedicine and glycan biomarkers is examined. Next, we discuss the reasons as to why unraveling of the sugar code might have lagged behind the DNA and protein codes. While social scientists have historically noted the importance of constructivism (e.g., how people interpret technology and build their values, hopes, and expectations into emerging technologies), life scientists relied on the material properties of technologies in explaining why some innovations emerge rapidly and are more popular than others. The concept of sociomateriality integrates these two explanations by highlighting the inherent entanglement of the social and the material contributions to knowledge and what is presented to us as reality from everyday laboratory life. Hence, we present a hypothesis based on a sociomaterial conceptual lens: because materiality and synthesis of glycans are not directly driven by a template, and thus more complex and open ended than sequencing of a finite length genome, social construction of expectations from unraveling of the sugar code versus the DNA code might have evolved differently, as being future-uncertain versus future-proof, respectively, thus potentially explaining the "sugar lag" in precision/personalized medicine diagnostics over the past decades. We conclude by introducing systems scientists, physicians, and biotechnology industry to the concept, practice, and value of responsible innovation, while glycomedicine and other emerging biomarker technologies (e.g., metagenomics and pharmacomicrobiomics) transition to applications in health care, ecology, pharmaceutical/diagnostic industries, agriculture, food, and bioengineering, among others.
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Affiliation(s)
- Vural Özdemir
- OMICS: A Journal of Integrative Biology, New Rochelle, New York.,Senior Advisor and Writer, Emerging Technology Governance and Responsible Innovation, Toronto, Ontario, Canada
| | - K Yalçın Arga
- Health Institutes of Turkey, Istanbul, Turkey.,Department of Bioengineering, Faculty of Engineering, Marmara University, İstanbul, Turkey
| | - Ramy K Aziz
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,The Center for Genome and Microbiome Research, Cairo University, Cairo, Egypt
| | - Mustafa Bayram
- Department of Food Engineering, Faculty of Engineering, Gaziantep University, Gaziantep, Turkey
| | - Shannon N Conley
- STS Futures Lab, School of Integrated Sciences, James Madison University, Harrisonburg, Virginia
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Laszlo Endrenyi
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Erik Fisher
- School for the Future of Innovation in Society and the Consortium for Science, Policy and Outcomes, Arizona State University, Tempe, Arizona
| | - Colin K Garvey
- Stanford Institute for Human-Centered Artificial Intelligence, Stanford University, Palo Alto, California
| | - Nezih Hekim
- Department of Biochemistry, Faculty of Medicine, İstanbul Medipol University, İstanbul, Turkey
| | - Tanja Kunej
- University of Ljubljana, Biotechnical Faculty, Department of Animal Science, Domzale, Slovenia
| | - Semra Şardaş
- Faculty of Pharmacy, İstinye University, İstanbul, Turkey
| | - Rene Von Schomberg
- Directorate General for Research and Innovation, European Commission, Brussel, Belgium.,Technical University Darmstadt, Darmstadt, Germany
| | - Aymen S Yassin
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,The Center for Genome and Microbiome Research, Cairo University, Cairo, Egypt
| | - Gürçim Yılmaz
- Writer and Editor, Cultural Studies, and Curator of Contemporary Arts, İstanbul, Turkey
| | - Wei Wang
- Key Municipal Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
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26
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Abstract
Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.
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Affiliation(s)
- Laura B Ramsey
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
- Divisions of Research in Patient Services and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
| | - Jacob T Brown
- Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, Minnesota 55812, USA
| | - Susan I Vear
- Department of Hematology & Oncology, Nationwide Children's Hospital, Columbus, Ohio 43205, USA
| | - Jeffrey R Bishop
- Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, and Department of Psychiatry, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
| | - Sara L Van Driest
- Departments of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
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27
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Qazi AS, Akbar S, Saeed RF, Bhatti MZ. Translational Research in Oncology. 'ESSENTIALS OF CANCER GENOMIC, COMPUTATIONAL APPROACHES AND PRECISION MEDICINE 2020:261-311. [DOI: 10.1007/978-981-15-1067-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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28
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Nofziger C, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agúndez JAG, Black JL, Dunnenberger HM, Ruano G, Kennedy MA, Phillips MS, Hachad H, Klein TE, Gaedigk A. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther 2020; 107:154-170. [PMID: 31544239 PMCID: PMC6925641 DOI: 10.1002/cpt.1643] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 08/29/2019] [Indexed: 01/13/2023]
Abstract
The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
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Affiliation(s)
| | - Amy J. Turner
- Department of Pediatrics, Section of Genomic Pediatrics and Children’s Research Institute, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- RPRD Diagnostics LLC, Wauwatosa, Wisconsin, USA
| | - Katrin Sangkuhl
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | | | - José A. G. Agúndez
- University Institute of Molecular Pathology Biomarkers, UEx, Cáceres; ARADyAL Instituto de Salud Carlos III. Spain
| | - John L. Black
- Personalized Genomics Laboratory, Division of Laboratory Genetics and Genomics, Mayo Clinic laboratories, Mayo Clinic, Rochester MN (200 1st Street SW, Rochester MN 55902)
| | - Henry M. Dunnenberger
- Mark R. Neaman Center for Personalized Medicine, NorthShore University HealthSystem, Evanton, IL, USA
| | - Gualberto Ruano
- Institute of Living at Hartford Hospital, Genomas Laboratory of Personalized Health, Hartford, Connecticut (67 Jefferson Street, Hartford, Connecticut 06106)
| | - Martin A. Kennedy
- Department of Pathology and Biomedical Science, University Otago, Christchurch, New Zealand
| | - Michael S. Phillips
- Sequence Bioinformatics Inc., 139 Water Street, 2 Floor, St. John’s NL, A1C 1B2, Canada
| | | | - Teri E. Klein
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - Andrea Gaedigk
- Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children’s Mercy Kansas City, Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
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29
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Moscoso CG, Potz KR, Tan S, Jacobson PA, Berger KM, Steer CJ. Precision medicine, agriculture, and genome editing: science and ethics. Ann N Y Acad Sci 2019; 1465:59-75. [PMID: 31721233 DOI: 10.1111/nyas.14266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/16/2019] [Indexed: 01/20/2023]
Abstract
The era of precision medicine has generated advances in various fields of science and medicine with the potential for a paradigm shift in healthcare delivery that will ultimately lead to an individualized approach to medicine. Such timely topics were explored in 2018 at a workshop held at the Third International Conference on One Medicine One Science (iCOMOS), in Minneapolis, Minnesota. A broad range of scientists and regulatory experts provided detailed insights into the challenges and opportunities associated with precision medicine and gene editing. There was a general consensus that advances in studying the genomic traits driving differential pharmacogenomics will undoubtedly enhance individualized treatments for a wide variety of diseases. Ethical considerations, societal implications, approaches for prioritizing safe and secure use of treatment modalities, and the advent of high-throughput computing and analysis of large, complex datasets were discussed. Large biobanks, such as the All of Us Research Program and the Veterans Affairs Million Veterans Program, can aid studies of various conditions in massive cohorts of patients. As the applications of precision medicine continue to mature, the full potential and promise of these individualized approaches will continue to yield important advances in transplant medicine, oncology, public health, agriculture, pharmacology, and bioinformatics.
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Affiliation(s)
- Carlos G Moscoso
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Kelly R Potz
- College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Shaoyuan Tan
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | | | - Clifford J Steer
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.,Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota
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30
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Lauschke VM, Zhou Y, Ingelman-Sundberg M. Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity. Pharmacol Ther 2019; 197:122-152. [PMID: 30677473 PMCID: PMC6527860 DOI: 10.1016/j.pharmthera.2019.01.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.
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Affiliation(s)
- Volker M Lauschke
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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31
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Lauschke VM, Ingelman-Sundberg M. Prediction of drug response and adverse drug reactions: From twin studies to Next Generation Sequencing. Eur J Pharm Sci 2019; 130:65-77. [PMID: 30684656 DOI: 10.1016/j.ejps.2019.01.024] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 01/12/2023]
Abstract
Understanding and predicting inter-individual differences related to the success of drug therapy is of tremendous importance, both during drug development and for clinical applications. Importantly, while seminal twin studies indicate that the majority of inter-individual differences in drug disposition are driven by hereditary factors, common genetic polymorphisms explain only less than half of this genetically encoded variability. Recent progress in Next Generation Sequencing (NGS) technologies has for the first time allowed to comprehensively map the genetic landscape of human pharmacogenes. Importantly, these projects have unveiled vast numbers of rare genetic variants, which are estimated to contribute substantially to the missing heritability of drug metabolism phenotypes. However, functional interpretation of these rare variants remains challenging and constitutes one of the important frontiers of contemporary pharmacogenomics. Furthermore, NGS technologies face challenges in the interrogation of genes residing in complex genomic regions, such as CYP2D6 and HLA genes. We here provide an update of the implementation of pharmacogenomic variations in the clinical setting and present emerging strategies that facilitate the translation of NGS data into clinically useful information. Importantly, we anticipate that these developments will soon result in a paradigm shift of pre-emptive genotyping away from the interrogation to candidate variants and towards the comprehensive profiling of an individuals genotype, thus allowing for a true individualization of patient drug treatment regimens.
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Affiliation(s)
- Volker M Lauschke
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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32
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Baskys A. Application of pharmacogenetics in clinical practice: problems and solutions. J Neural Transm (Vienna) 2018; 126:109-113. [PMID: 29922908 DOI: 10.1007/s00702-018-1894-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/12/2018] [Indexed: 12/16/2022]
Abstract
This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.
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Affiliation(s)
- Andrius Baskys
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA. .,Memory Disorders Clinic, Riverside Psychiatric Medical Group, Riverside, CA, USA. .,World Association of Genomic Medicine, A Coruña, Spain.
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33
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Kaye AD, Mahakian T, Kaye AJ, Pham AA, Hart BM, Gennuso S, Cornett EM, Gabriel RA, Urman RD. Pharmacogenomics, precision medicine, and implications for anesthesia care. Best Pract Res Clin Anaesthesiol 2018; 32:61-81. [DOI: 10.1016/j.bpa.2018.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/30/2018] [Indexed: 01/28/2023]
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34
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Bank PCD, Swen JJ, Guchelaar HJ. Implementation of Pharmacogenomics in Everyday Clinical Settings. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 83:219-246. [PMID: 29801576 DOI: 10.1016/bs.apha.2018.04.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations. Finally, clinical studies which provide scientific evidence and information on cost-effectiveness supporting clinical implementation of PGx in clinical care are discussed along with the remaining barriers for adoption of PGx testing by healthcare professionals.
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Affiliation(s)
- Paul C D Bank
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
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35
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Ko FS. Evaluate the relative efficiency of a targeted clinical trial design to an untargeted design under the issue of cost. COMMUN STAT-THEOR M 2017. [DOI: 10.1080/03610926.2017.1295080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Feng-Shou Ko
- Department of Biostatistics, KF Statistical Consulting Company, Kaohsiung, Taiwan R.O.C
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36
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Ko FS. Discussion on the issue of sample size determination for a targeted to an untargeted and to a mixed effect model-based clinical trial design. J Appl Stat 2017. [DOI: 10.1080/02664763.2017.1405915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Feng-shou Ko
- KF Statistical Consulting Company, Kaohsiung, Taiwan, Republic of China
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37
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Weinshilboum RM, Wang L. Pharmacogenomics: Precision Medicine and Drug Response. Mayo Clin Proc 2017; 92:1711-1722. [PMID: 29101939 PMCID: PMC5682947 DOI: 10.1016/j.mayocp.2017.09.001] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 08/17/2017] [Accepted: 09/05/2017] [Indexed: 11/21/2022]
Abstract
Pharmacogenomics is the use of genomic and other "omic" information to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy. The science underlying pharmacogenomics has evolved rapidly over the 50 years since it was first suggested that genetics might influence drug response phenotypes. That process has occurred in parallel with advances in DNA sequencing and other molecular technologies, with striking increases in our understanding of the human genome. There are now many validated examples of the clinical utility of pharmacogenomics, and this type of clinical genomic information is increasingly being generated in clinical laboratories, incorporated into electronic health records, and used to "tailor" or individualize drug therapy. This review will survey the origins and development of pharmacogenomics; it will address some of the challenges associated with the clinical implementation of pharmacogenomics; and it will attempt to foresee future advances in this important genomic discipline, one that almost certainly will be among the earliest and most widely adopted aspects of clinical genomics.
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Affiliation(s)
- Richard M Weinshilboum
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
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38
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Bank PCD, Caudle KE, Swen JJ, Gammal RS, Whirl-Carrillo M, Klein TE, Relling MV, Guchelaar HJ. Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Clin Pharmacol Ther 2017; 103:599-618. [PMID: 28994452 DOI: 10.1002/cpt.762] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 05/24/2017] [Accepted: 06/01/2017] [Indexed: 12/16/2022]
Abstract
Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well-known gene-drug pairs. Published recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.
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Affiliation(s)
- P C D Bank
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - K E Caudle
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - J J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - R S Gammal
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Pharmacy Practice, MCPHS University, Boston, Massachusetts, USA
| | - M Whirl-Carrillo
- Pharmacogenomics Knowledgebase (PharmGKB), Stanford University School of Medicine, Palo Alto, California, USA
| | - T E Klein
- Pharmacogenomics Knowledgebase (PharmGKB), Stanford University School of Medicine, Palo Alto, California, USA
| | - M V Relling
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - H-J Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
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39
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Rabbani B, Nakaoka H, Akhondzadeh S, Tekin M, Mahdieh N. Next generation sequencing: implications in personalized medicine and pharmacogenomics. MOLECULAR BIOSYSTEMS 2017; 12:1818-30. [PMID: 27066891 DOI: 10.1039/c6mb00115g] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A breakthrough in next generation sequencing (NGS) in the last decade provided an unprecedented opportunity to investigate genetic variations in humans and their roles in health and disease. NGS offers regional genomic sequencing such as whole exome sequencing of coding regions of all genes, as well as whole genome sequencing. RNA-seq offers sequencing of the entire transcriptome and ChIP-seq allows for sequencing the epigenetic architecture of the genome. Identifying genetic variations in individuals can be used to predict disease risk, with the potential to halt or retard disease progression. NGS can also be used to predict the response to or adverse effects of drugs or to calculate appropriate drug dosage. Such a personalized medicine also provides the possibility to treat diseases based on the genetic makeup of the patient. Here, we review the basics of NGS technologies and their application in human diseases to foster human healthcare and personalized medicine.
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Affiliation(s)
- Bahareh Rabbani
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Niayesh-Vali asr Intersection, Tehran, Iran.
| | - Hirofumi Nakaoka
- Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mustafa Tekin
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Nejat Mahdieh
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Niayesh-Vali asr Intersection, Tehran, Iran.
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40
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Abstract
Pharmacogenomics (PGx), a substantial component of "personalized medicine", seeks to understand each individual's genetic composition to optimize drug therapy -- maximizing beneficial drug response, while minimizing adverse drug reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits -- influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance -- thus having limited predictive power and clinical utility.
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Affiliation(s)
- Ge Zhang
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, United States.
| | - Daniel W Nebert
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, United States; Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati School of Medicine, Cincinnati, OH 45267-0056, United States.
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41
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Yang Y, Botton MR, Scott ER, Scott SA. Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics 2017; 18:673-685. [PMID: 28470112 DOI: 10.2217/pgs-2017-0033] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.
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Affiliation(s)
- Yao Yang
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mariana R Botton
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Erick R Scott
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Stuart A Scott
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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42
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Buermans HPJ, Vossen RHAM, Anvar SY, Allard WG, Guchelaar HJ, White SJ, den Dunnen JT, Swen JJ, van der Straaten T. Flexible and Scalable Full-Length CYP2D6 Long Amplicon PacBio Sequencing. Hum Mutat 2017; 38:310-316. [PMID: 28044414 PMCID: PMC5324676 DOI: 10.1002/humu.23166] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 11/18/2016] [Accepted: 12/22/2016] [Indexed: 01/08/2023]
Abstract
Cytochrome P450 2D6 (CYP2D6) is among the most important genes involved in drug metabolism. Specific variants are associated with changes in the enzyme's amount and activity. Multiple technologies exist to determine these variants, like the AmpliChip CYP450 test, Taqman qPCR, or Second‐Generation Sequencing, however, sequence homology between cytochrome P450 genes and pseudogene CYP2D7 impairs reliable CYP2D6 genotyping, and variant phasing cannot accurately be determined using these assays. To circumvent this, we sequenced CYP2D6 using the Pacific Biosciences RSII and obtained high‐quality, full‐length, phased CYP2D6 sequences, enabling accurate variant calling and haplotyping of the entire gene‐locus including exonic, intronic, and upstream and downstream regions. Unphased diplotypes (Roche AmpliChip CYP450 test) were confirmed for 24 of the 25 samples, including gene duplications. Cases with gene deletions required additional specific assays to resolve. In total, 61 unique variants were detected, including variants that had not previously been associated with specific haplotypes. To further aid genomic analysis using standard reference sequences, we have established an LOVD‐powered CYP2D6 gene‐variant database, and added all reference haplotypes and data reported here. We conclude that our CYP2D6 genotyping approach produces reliable CYP2D6 diplotypes and reveals information about additional variants, including phasing and copy‐number variation.
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Affiliation(s)
- Henk P J Buermans
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - Rolf H A M Vossen
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - Seyed Yahya Anvar
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - William G Allard
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands
| | - Stefan J White
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - Johan T den Dunnen
- Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands.,Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands
| | - Tahar van der Straaten
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands
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Motoi Y, Watanabe K, Honma H, Tadano Y, Hashimoto H, Kubota T. Digital PCR for determination of cytochrome P450 2D6 and sulfotransferase 1A1 gene copy number variations. Drug Discov Ther 2017; 11:336-341. [DOI: 10.5582/ddt.2017.01057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Yutaro Motoi
- Niigata University of Pharmacy and Applied Life Sciences
| | | | - Hiroyuki Honma
- Niigata University of Pharmacy and Applied Life Sciences
| | - Yousuke Tadano
- Niigata University of Pharmacy and Applied Life Sciences
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45
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Abstract
Sex, the states of being female or male, potentially interacts with all xenobiotic exposures, both inadvertent and deliberate, and influences their toxicokinetics (TK), toxicodynamics, and outcomes. Sex differences occur in behavior, exposure, anatomy, physiology, biochemistry, and genetics, accounting for female-male differences in responses to environmental chemicals, diet, and pharmaceuticals, including adverse drug reactions (ADRs). Often viewed as an annoying confounder, researchers have studied only one sex, adjusted for sex, or ignored it. Occupational epidemiology, the basis for understanding many toxic effects in humans, usually excluded women. Likewise, Food and Drug Administration rules excluded women of childbearing age from drug studies for many years. Aside from sex-specific organs, sex differences and sex × age interactions occur for a wide range of disease states as well as hormone-influenced conditions and drug distribution. Women have more ADRs than men; the classic sex hormone paradigm (gonadectomy and replacement) reveals significant interaction of sex and TK including absorption, distribution, metabolisms, and elimination. Studies should be designed to detect sex differences, describe the mechanisms, and interpret these in a broad social, clinical, and evolutionary context with phenomena that do not differ. Sex matters, but how much of a difference is needed to matter remains challenging.
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Affiliation(s)
- Michael Gochfeld
- Environmental and Occupational Health Sciences Institute and Consortium for Risk Evaluation with Stakeholder Participation at Rutgers—Robert Wood Johnson Medical School. Piscataway, New Jersey
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46
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Abstract
It is well established that variations in genes can alter the pharmacokinetic and pharmacodynamic profile of a drug and immunological responses to it. Early advances in pharmacogenetics were made with traditional genetic techniques such as functional cloning of genes using knowledge gained from purified proteins, and candidate gene analysis. Over the past decade, techniques for analysing the human genome have accelerated greatly as knowledge and technological capabilities have grown. These techniques were initially focussed on understanding genetic factors of disease, but increasingly they are helping to clarify the genetic basis of variable drug responses and adverse drug reactions (ADRs). We examine genetic methods that have been applied to the understanding of ADRs, review the current state of knowledge of genetic factors that influence ADR development, and discuss how the application of genome-wide association studies and next-generation sequencing approaches is supporting and extending existing knowledge of pharmacogenetic processes leading to ADRs. Such approaches have identified single genes that are major contributing genetic risk factors for an ADR, (such as flucloxacillin and drug-induced liver disease), making pre-treatment testing a possibility. They have contributed to the identification of multiple genetic determinants of a single ADR, some involving both pharmacologic and immunological processes (such as phenytoin and severe cutaneous adverse reactions). They have indicated that rare genetic variants, often not previously reported, are likely to have more influence on the phenotype than common variants that have been traditionally tested for. The problem of genotype/phenotype discordance affecting the interpretation of pharmacogenetic screening and the future of genome-based testing applied to ADRs are also discussed.
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Abstract
A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed.
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Nassar AF, Wu T, Nassar SF, Wisnewski AV. UPLC-MS for metabolomics: a giant step forward in support of pharmaceutical research. Drug Discov Today 2016; 22:463-470. [PMID: 27919805 DOI: 10.1016/j.drudis.2016.11.020] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 10/23/2016] [Accepted: 11/25/2016] [Indexed: 01/05/2023]
Abstract
Metabolomics is a relatively new and rapidly growing area of post-genomic biological research. As use of metabolomics technology grows throughout the spectrum of drug discovery and development, and its applications broaden, its impact is expanding dramatically. This review seeks to provide the reader with a brief history of the development of metabolomics, its significance and strategies for conducting metabolomics studies. The most widely used analytical tools for metabolomics: NMR, LC-MS and GC-MS, are discussed along with considerations for their use. Herein, we will show how metabolomics can assist in pharmaceutical research studies, such as pharmacology and toxicology, and discuss some examples of the importance of metabolomics analysis in research and development.
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Affiliation(s)
- Ala F Nassar
- School of Medicine, Department of Internal Medicine, Yale University, New Haven, CT, USA; Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT, USA.
| | - Terence Wu
- West Campus Analytical Core, Yale University, West Haven, CT, USA
| | - Samuel F Nassar
- Yale School of Medicine, Departments of Neurology and Immunobiology, New Haven, CT 06511, USA
| | - Adam V Wisnewski
- School of Medicine, Department of Internal Medicine, Yale University, New Haven, CT, USA
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49
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Abstract
The biochemical facets of toxicology have always had a major role in providing insight into mechanisms. Some of the history of the development of this area is summarized, including metabolism, enzymology, and the chemistry of reactive intermediates. Knowledge in these fields has had a major impact in the areas of drug metabolism and safety assessment, which are both critical steps in the development of pharmaceuticals and the rational use of commodity chemicals. The science of toxicology has developed considerably with input from other disciplines and today is poised to emerge as a predictive science with even more dramatic impact. The challenges ahead are considerable but there is renewed excitement in the potential of the field. As in the past, further advances in the field of toxicology will require the input of knowledge from many disciplines.
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Affiliation(s)
- F Peter Guengerich
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
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50
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Fishbein L. An Overview of Some Metabolic and Modulating Factors in Toxicity and Chemical Carcinogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.3109/10915818309140669] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Lawrence Fishbein
- Department of Health and Human Services, Food and Drug Administration, National Center for Toxicologi-cal Research, Jefferson, AR, 72079
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