In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma

Chládek, Jaroslav; Zimová, Gabriela; Beránek, M.; Martı́nková, Jiřina

doi:10.1007/s002280000218

Cited by 34 publications

(39 citation statements)

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“…Chladek et al (2000) have confirmed that the use of dextromethorphan:dextrorphan metabolic ratio could be practiced without regard to the matrix of collection. In a study involving 95 subjects, the authors demonstrated that the phenotypes predicted from the urine collected over a 0 -4 h time interval following drug ingestion appeared to be reasonably well correlated with the phenotypes predicted from a single point determination from plasma at 3 h post dosing (Cladek et al, 2000).…”

Section: Options For Phenotyping-urine Vs Plasmasupporting

confidence: 69%

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

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The concepts of drug development have evolved over the last few decades. Although number of novel chemical entitities belonging to varied classes have made it to the market, the process of drug development is challenging, intertwined as it is with complexities and uncertainities. The intention of this article is to provide a comprehensive review of novel chemical entities (NCEs) that are substrates to cytochrome P450 (CYP) 2D6 isozyme. Topics covered in this review aim: (1) to provide a framework of the importance of CYP2D6 isozyme in the biotransformation of NCEs as stand-alones and/or in conjunction with other CYP isozymes; (2) to provide several case studies of drug disposition of important drug substrates, (3) to cover key analytical perspectives and key assay considerations to assess the role and involvement of CYP2D6, and (4) to elaborate some important considerations from the development point of view. Additionally, wherever applicable, special emphasis is provided on chiral drug substrates in the various subsections of the review.

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Section: Options For Phenotyping-urine Vs Plasmasupporting

confidence: 69%

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

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“…In contrast, the analysis of EM healthy subjects data from Kohler et al (1997) showed a very low correlation between the UMR in 8-h urine collection and in serum 1 h after DTM administration (r ϭ 0.19). Chladek et al (2000) found good correlation between UMR and 3-h plasma ratio (r ϭ 0.88), and Capon et al (1996) observed a similar correlation between the UMR and partial clearance of DTM to DT (r 2 ϭ 0.82). However, these studies included poor metabolizers in the analysis, and the correlations among EMs alone would be significantly lower.…”

Section: Discussionmentioning

confidence: 65%

“…Indeed, the dextromethorphan to dextrorphan urinary metabolic ratio (UMR) is routinely applied to segregate populations into two major phenotypic groups: extensive and poor metabolizers (Hou et al, 1996;Sachse et al, 1997;Tateishi et al, 1999). Although noninvasive and easy to perform, the utility of the urinary metabolic ratio to assess moderate alterations in CYP2D6 activity has not been established (Kohler et al, 1997;Tenneze et al, 1999;Chladek et al, 2000;Yeh et al, 2003).…”

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confidence: 99%

Dextromethorphan to Dextrorphan Urinary Metabolic Ratio Does Not Reflect Dextromethorphan Oral Clearance

Borges

Li²,

Hamman

et al. 2005

Drug Metab Dispos

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ABSTRACT:Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of dextromethorphan urinary metabolic ratio to predict dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with dextromethorphan oral clearance (r ‫؍‬ 0.24; p ‫؍‬ 0.04). In contrast, the dextromethorphan oral clearance was highly correlated with the dextromethorphan to dextrorphan area under the concentration-time curve ratio (r ‫؍‬ 0.84; p ‫؍‬ 0.005) and the 3-h (r ‫؍‬ 0.60; p ‫؍‬ 0.003), 4-h (r ‫؍‬ 0.72, p < 0.001), 6-h (r ‫؍‬ 0.67; p < 0.001), and 8-h (r ‫؍‬ 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.

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“…Hu et al [122] have shown that the plasma sample at 2, 3, 4 or 5 h or the saliva sample at 6 h could be used for determining the DMR. In one study in healthy Caucasian subjects, the DMR from urine collected over the time interval 0-4 h after the dose correlated reasonably well with those determined from plasma concentrations obtained at 3 h [123]. More recently, it has been shown that the DMRs determined using 0-8 h urine collection or a serum sample at 3 h postdose also correlate well with each other [124].…”

Section: Phenotyping Protocolsmentioning

confidence: 74%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

220

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma

Cited by 34 publications

References 0 publications

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Dextromethorphan to Dextrorphan Urinary Metabolic Ratio Does Not Reflect Dextromethorphan Oral Clearance

Addressing phenoconversion: the Achilles' heel of personalized medicine

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