Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis*

Hou, Zone Yuan; Chen, Ching Pu; Wu, Yang Chang; Lai, Ming Derg; Buchert, Elaine T.; Chung, Hsiao Min; Pickle, Linda Williams; Woosley, Raymond L.

doi:10.1016/s0009-9236(96)90109-5

Cited by 12 publications

(5 citation statements)

References 23 publications

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“…Although the parent compound and its metabolite concentrations can be determined in different biological fluids (e.g., serum and saliva), their ratio in urine is the most frequently used method to assess CYP2D6 status in vivo. 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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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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“…This is similar to the time change profiles, which show two groups of plasma metabolic ratios separated by an average line for both formulations at steady state. However, a maximum likelihood decomposition of a frequency distribution of urinary metabolic ratios reported by Hou et al [9] showed that a mixture of 3 normal distributions was significantly better at fitting the observed distribution than was a mixture of 2 normal distributions (p ! 0.025).…”

Section: Resultsmentioning

confidence: 99%

“…Urinary DM:DX ratios so obtained have been recognized as a feasible noninvasive method for assessing CYP2D6 activity in vivo. Because urine collection may not be feasible or reliable in patients with renal failure, an alternative method of analyzing saliva samples collected 3 h after taking DM was developed and has been proven to be satisfactory [9]. A salivary metabolic ratio of 14.0 for free compounds concordantly reached the same phenotypic assignment as using a urinary metabolic ratio of 4.0.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Pharmacokinetic Parameters for Assessment of Dextromethorphan Metabolic Phenotypes

Yeh

Tao

et al. 2003

J Biomed Sci

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In this study, the metabolic ratios of dextromethorphan to dextrorphan (DM/DX) in plasma were calculated at steady state after administering 2 dosage forms (Medicon^® and Detusiv^®) of DM with different release rates. The urinary metabolic ratio for each subject was also determined based on the total drug concentration in the urine. An analysis of pharmacokinetic parameters for determining the DM metabolic phenotype was conducted. Results demonstrate that double logarithmic correlations between the metabolic ratios based on pharmacokinetic parameters of either AUC_0-τ,ss, C_max,ss, C_min,ss, or C_ave,ss for Medicon and Detusiv and the urinary metabolic ratios were all significant. Probit plots of the metabolic ratios based on these pharmacokinetic parameters revealed 2 clusters of distribution, representing extensive and intermediate metabolizers. An antimode of 2.0 for total drug based on these pharmacokinetic parameters was determined and correspondingly referred to an antimode of 0.02 for the urinary metabolic ratio to delineate extensive and intermediate metabolizers. This model was also verified to be appropriate when using total plasma concentrations of DM and DX at any time during the period of the dosing interval at steady state to calculate the metabolic ratio for identifying extensive and intermediate metabolizers. Therefore, the metabolic ratio based on the pharmacokinetic parameters of either AUC_0-τ,ss, C_max,ss, C_min,ss, or C_ave,ss and plasma concentrations of DM and DX in a single blood sample at steady state are proposed as an alternative way to identify phenotypes of CYP2D6.

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“…The latter 2 groups, however, could not be separated on the basis of oral fluid results [99]. The applicability of this method and its potential to provide an alternative for urine-based CYP2D6 phenotyping was demonstrated in 100 anuric patients with renal failure [100]. However, in a study with repetitive dextromethorphan administration, Hu et al observed poor repeatability of 3, 4, and 5 h oral fluid dextromethorphan/dextrorphan ratios.…”

Section: Oral Fluidmentioning

confidence: 99%

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

2015

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Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes, as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques.In this review, we provide a comprehensive overview of available methods using dried blood spots, hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or dried blood spots, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non-or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. 4 Key Points Phenotyping by administration of a selective probe drug, followed by determination of a specific phenotyping metric, allows to assess the in vivo enzyme activity of CYP450 enzymes, taking into account genetic, non-genetic and environmental influencing factors. In addition to classical sampling techniques, such as blood or urine collection, reliable phenotyping procedures for several clinically relevant CYP450 enzymes are currently available for oral fluid, breath and dried blood spots.

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Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis*

Cited by 12 publications

References 23 publications

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

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

Analysis of Pharmacokinetic Parameters for Assessment of Dextromethorphan Metabolic Phenotypes

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

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