Cytochrome P450 2D6

Owen, Ryan; Sangkuhl, Katrin; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e32832e0e97

Cited by 109 publications

(86 citation statements)

References 30 publications

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“…Cytochrome P450 2D6 is known to be absent from the liver and brain for a small percentage (∼10%) of the population [40], but its function in the human brain remains elusive even though personality differences have been reported between EMs and PMs, suggesting the potential existence of endogenous substrates for CYP2D6 [41]. To address this, the CYP2D6-humanized mouse model has been further applied to the search for potential endogenous substrates for CYP2D6 [42][43][44].…”

Section: Cyp2d6 Humanized (Knock-in) Mouse Modelmentioning

confidence: 99%

Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters

Bessire

Youdim

Hurst

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Genetically modified animals (GEMA) provide in vivo tools to understand the role of enzymes, transcriptional factors, and transporters in drug disposition and drug toxicities. Several phase I and II enzymes, transcriptional factors, and the clinically relevant drug transporters have been reviewed in this chapter by highlighting how the animal models have elucidated or validated their role in drug disposition, endogenous substrate regulation, or drug toxicities. The utility of animal models in research and drug development provides in vivo tools to gain a better understanding of the role of drug‐metabolizing enzymes, transcriptional factors, and transporters in the absorption, disposition, metabolism, and drug‐related toxicities.

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Section: Cyp2d6 Humanized (Knock-in) Mouse Modelmentioning

confidence: 99%

Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters

Bessire

Youdim

Hurst

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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“…Of these, more than 50% are due to just three markers: CYP2D6 (40 treatments), G6PD (glucose 6-phosphate dehydrogenase) (20) and CYP2C19 (16). All these biomarkers are related to drug metabolism, as are three other biomarkers affecting relatively large numbers of treatments, namely CYP2C9 (4), TPMT (thiopurine methyltransferase) (4) and UGT1A1 (5). Currently, therefore, drug metabolism is overwhelmingly the most significant area related to the human physiome in which pharmacogenomic information influences treatment regime.…”

Section: Personalized Medicine In Current Clinical Practicementioning

confidence: 99%

“…Different alleles can result in complete loss, partial loss or hyperfunctional activity [5] rsfs.royalsocietypublishing.org Interface Focus 6: 20150094…”

Section: Non-universal Therapy In Drug Discovery and Developmentmentioning

confidence: 99%

A physiome interoperability roadmap for personalized drug development

et al. 2016

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One contribution of 12 to a theme issue 'The Human Physiome: a necessary key to the creative destruction of medicine'. The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as '-omics'), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development.

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“…Their essential role in drug metabolism makes CYP enzymes of great pharmacokinetic importance. A large number of CYP variants linked to altered drug pharmacokinetics have been reported for several CYP family members, including CYP1A2 [145], CYP2B6 [146], CYP2C9 [147], CYP2C19 [145], CYP2D6 [148], CYP2J2 [149] and CYP3A5 [150]. As a family, CYP enzymes bind a remarkably broad range of ligands.…”

Section: Pharmacokinetic Effects Of Missense Mutationsmentioning

confidence: 99%

Bioinformatics and variability in drug response: a protein structural perspective

Lahti

Tang

Capriotti

et al. 2012

J. R. Soc. Interface.

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Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk -benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein -drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein -drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants.

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Cytochrome P450 2D6

Cited by 109 publications

References 30 publications

Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters

Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters

A physiome interoperability roadmap for personalized drug development

Bioinformatics and variability in drug response: a protein structural perspective

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