The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans*

Capon, Deborah A.; Bochner, Felix; Kerry, Nicole; Mikus, Gerd; Danz, Catherine; Somogyi, Andrew A.

doi:10.1016/s0009-9236(96)90056-9

Cited by 120 publications

(122 citation statements)

References 51 publications

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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: 67%

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

Borges

Li²,

Hamman

et al. 2005

Drug Metabolism and Disposition

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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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Section: Discussionmentioning

confidence: 67%

“…The formation of dextrorphan by CYP2D6 is responsible for approximately 97% of the oral clearance of dextromethorphan in EMs (Capon et al, 1996;Gorski et al, 2004). The dextromethorphan urinary metabolic ratio is a commonly used method for quantifying CYP2D6 activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

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

Borges

Li²,

Hamman

et al. 2005

Drug Metabolism and Disposition

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“…DEX is extensively O-demethylated to dextrorphan by CYP2D6. The formation of DXO by CYP2D6 is responsible for approximately 97% of the oral clearance of DEX in EMs (Capon et al, 1996;Gorski et al, 2004). Dextrorphan then undergoes glucuronidation mostly by UGT2B7 (Lutz and Isoherranen, 2012).…”

Section: Downloaded Frommentioning

confidence: 99%

“…CL int,u,2D6 was estimated in Simcyp by simultaneously fitting observed plasma concentration-time profiles extracted from previous publications (Abdul Manap et al, 1999;Moghadamnia et al, 2003) (see Table 4). Optimization of CL int,u,2D6 was necessary to match predicted bioavailability (F a *F h *F g ;7%) to that reported (,5%) (Capon et al, 1996). CL r of DEX was assumed to approximate f u,p *GFR (see footnote to Table 4).…”

Section: Downloaded Frommentioning

confidence: 99%

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A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Nallani

Zhao

et al. 2013

Drug Metabolism and Disposition

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Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T 3 ). Predicted mean postpartum to third trimester (PP:T 3 ) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (C ss ) ratio (PP:T 3 ) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T 3 ) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T 3 ) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T 3 was required to recover the observed PP:T 3 ratios of PAR C ss , DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T 3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

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Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Pall

2009

General, Applied and Systems Toxicology

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Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H 2 S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low‐level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility. The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO − cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high‐level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO − cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low‐level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.

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The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans*

Abstract: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.

Cited by 120 publications

References 51 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

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

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