Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone

Coller, Janet K.; Joergensen, Christel; Foster, David J. R.; James, Heather M.; Gillis, David C.; Christrup, Lona Louring; Somogyi, A.

doi:10.5414/cpp45410

Cited by 24 publications

(14 citation statements)

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“…Several reports suggest that its contribution is negligible [17], [58], while others have shown that specific inhibitors of CYP2D6 as paroxetine, markedly influence methadone disposition [29], [30]. Five CYP2D6 UM subjects were identified among responder patients while none among nonresponders.…”

Section: Discussionmentioning

confidence: 94%

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

et al. 2011

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Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

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Section: Discussionmentioning

confidence: 94%

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

et al. 2011

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“…In contrast to tramadol for other CYP2D6 substrates with active metabolites among the administered opioids (Table 1), evidence for altered analgesic effects with altered CYP2D6 function is either negative such as for dihydrocodeine [53][54][55] or, so far at a nongenetic level, for oxycodone [56], or restricted to single case reports communicating a reasonable mechanism-based interpretation of ineffectiveness [57] or inadequate responses to oxycodone administration [58] rather than systematic evidence. In addition, negative evidence is available for methadone being also partly cleared through CYP2D6 [59,60].…”

Section: Discussionmentioning

confidence: 98%

Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers

Lötsch

Hentig²,

Freynhagen³

et al. 2009

Pharmacogenetics and Genomics

110

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Genetics were reflected in the outpatient pain therapy only to a modest degree. The need of outpatient therapy of pain of various causes guided by the presently known functional genetic variants cannot be convincingly concluded from the present data. Using the ABCB1 3435 genotype to predefine lower individual opioid doses barely merits the laboratory effort. If any, the results suggest that a genetics guided outpatient pain therapy may be based on ABCB1 and OPRM1 variants.

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“…However, there is controversy as to which CYP 450 enzymes are primarily responsible for the stereoselective biotransformation of R - and S -methadone (Wang et al 2003; Coller et al 2007; Rollason et al 2008; Kharasch et al 2008a; Kharasch et al 2008b). While these studies together suggest CYP 450 enzymes 2B6 and 2C19 may have the most influence on stereoselective methadone metabolism in the human, the specific CYP 450 enzymes required for metabolism of methadone in the guinea pig have not yet been identified.…”

Section: Discussionmentioning

confidence: 99%

S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig

Silverman

Nettleton

Spencer

et al. 2009

Respiratory Physiology & Neurobiology

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Methadone is administered as a racemic mixture, although its analgesic and respiratory effects are attributed to R-isomer activity at the mu-opioid receptor (MOP). Recently, we observed a fourfold increase in inspiratory time in three-day old guinea pigs following an injection of racemic methadone. We hypothesized that this effect was due to augmentation of R-methadone induced respiratory depression by the S-methadone isomer. In the current longitudinal study, we injected three-, seven-, and fourteen-day old neonatal guinea pigs with saline, R-methadone, S-methadone, or R-plus S-methadone in order to characterize the roles of the individual isomers, as well as the synergistic effects of co-administration. Using plethysmography, we measured respiratory parameters while breathing room air and during a 5% CO 2 challenge. S-methadone alone had no respiratory effects. However, the R-plus S-methadone group showed greater respiratory depression and increased inspiratory time than the R-methadone group in the youngest animals, suggesting that the respiratory effects of R-methadone are augmented by S-methadone in early development.

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Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone

Cited by 24 publications

References 0 publications

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers

S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig

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