The Potential for CYP2D6 Inhibition Screening Using a Novel Scintillation Proximity Assay-Based Approach

Delaporte, Enock; Slaughter, Donald; Egan, Marjorie A.; Gatto, Gregory J.; Santos, Albie; Shelley, Joanne; Price, Elizabeth; Howells, Leighton; Dean, Dennis C.; Rodrigues, A. David

doi:10.1089/10870570152488428

Cited by 5 publications

(10 citation statements)

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“…The main drawback of this assay is that it does not use drug-like probe substrates. Assays using radiolabeled substrates have also been used for CYP inhibition screening [61][62][63][64]. A fully automated radiometric inhibition assay has been developed for CYP2D6 using [O-Me-14 C]-dextromethorphan as the radioactive probe [63].…”

Section: In Vitro Assays For Measuring Cyp2d6-mediated Inhibitionmentioning

confidence: 99%

“…Assays using radiolabeled substrates have also been used for CYP inhibition screening [61][62][63][64]. A fully automated radiometric inhibition assay has been developed for CYP2D6 using [O-Me-14 C]-dextromethorphan as the radioactive probe [63]. This radiometric assay offers some advantages over the fluorometric assay including substrate selectivity, better solubility of substrates, and higher substrate turnover.…”

Section: In Vitro Assays For Measuring Cyp2d6-mediated Inhibitionmentioning

confidence: 99%

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Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Bourdonnec¹,

Leister²

2009

CMC

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Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.

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Section: In Vitro Assays For Measuring Cyp2d6-mediated Inhibitionmentioning

confidence: 99%

Section: In Vitro Assays For Measuring Cyp2d6-mediated Inhibitionmentioning

confidence: 99%

Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Bourdonnec¹,

Leister²

2009

CMC

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“…Concentrations of dextromethorphan and dextrorphan were calculated in a hypothetical effect compartment (see appendix). The PK and PD data were linked assuming a sigmoidal E max model such that the response to dextromethorphan in each individual (E i ) was described by equation (11). (11) where Ce i , E max,i , EC 50,i , and n i are the concentration of active moiety (dextromethorphan and/or dextrorphan) (equation (A6), appendix), the maximal antitussive effect (Table III), the concentration of active moiety in the effect compartment associated with half E max (Table III), and the Hill coefficient (Table III), respectively, in each individual.…”

Section: Pharmacodynamic Modelmentioning

confidence: 99%

“…The PK and PD data were linked assuming a sigmoidal E max model such that the response to dextromethorphan in each individual (E i ) was described by equation (11). (11) where Ce i , E max,i , EC 50,i , and n i are the concentration of active moiety (dextromethorphan and/or dextrorphan) (equation (A6), appendix), the maximal antitussive effect (Table III), the concentration of active moiety in the effect compartment associated with half E max (Table III), and the Hill coefficient (Table III), respectively, in each individual. The combined effects of dextromethorphan and dextrorphan were modeled assuming competitive interaction at the same receptor site: (12) where Pot DOR,i is the potency of dextrorphan relative to dextromethorphan in the ith individual (EC 50 (DEX)/EC 50 (DOR)) ( Table III).…”

Section: Pharmacodynamic Modelmentioning

confidence: 99%

Incorporating In Vitro Information on Drug Metabolism Into Clinical Trial Simulations to Assess the Effect of CYP2D6 Polymorphism on Pharmacokinetics and Pharmacodynamics: Dextromethorphan as a Model Application

Dickinson

Rezaee²,

Proctor

et al. 2007

The Journal of Clinical Pharma

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In vitro-in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was integrated to assess the power of studies to detect differences between phenotypes. Whereas 6 subjects of each phenotype were adequate to achieve 80% power in showing pharmacokinetic differences, the power required to detect a difference in antitussive response was less than 80% with 500 subjects in each study arm. Combining in vitro-in vivo extrapolation with a clinical trial simulation is useful in assessing different elements of study design and could be used a priori to avoid inconclusive pharmacogenetic studies.

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“…• fluorescence polarisation (FP) [62] • time-resolved fluorescence [63,64] • fluorescence resonance energy transfer [65,66] • single molecular diffusion [67,68] • scintillation proximity assays [69,70] • biomolecular interaction analysis [71] The VITA-enabled assay is universally applicable to any target including those that are impossible to assay using traditional approaches, such as monitoring biochemical activity. Most of the above-mentioned assays are amenable to automation and suitable for high-throughput screens.…”

Section: Peptides In Surrogate-ligand Based Screeningmentioning

confidence: 99%

Peptide ligands in antibacterial drug discovery: use as inhibitors in target validation and target-based screening

Lapan¹,

Chapple²,

Galcheva-Gargova³

et al. 2002

Expert Opinion on Therapeutic Targets

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There is an urgent need to develop novel classes of antibiotics to counter the inexorable rise of resistant bacterial pathogens. Modern antibacterial drug discovery is focused on the identification and validation of novel protein targets that may have a suitable therapeutic index. In combination with assays for function, the advent of microbial genomics has been invaluable in identifying novel antibacterial drug targets. The major challenge in this field is the implementation of methods that validate protein targets leading to the discovery of new chemical entities. Ligand-directed drug discovery has the distinct advantage of having a concurrent analysis of both the importance of a target in the disease process and its amenability to functional modulation by small molecules. VITA is a process that enables a target-based paradigm by using peptide ligands for direct in vitro and in vivo validation of antibacterial targets and the implementation of high-throughput assays to identify novel inhibitory molecules. This process can establish sufficient levels of confidence indicating that the target is relevant to the disease process and inhibition of the target will lead to effective disease treatment.

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The Potential for CYP2D6 Inhibition Screening Using a Novel Scintillation Proximity Assay-Based Approach

Cited by 5 publications

References 0 publications

Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Incorporating In Vitro Information on Drug Metabolism Into Clinical Trial Simulations to Assess the Effect of CYP2D6 Polymorphism on Pharmacokinetics and Pharmacodynamics: Dextromethorphan as a Model Application

Peptide ligands in antibacterial drug discovery: use as inhibitors in target validation and target-based screening

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