Substitution of (R,S)-Methadone by (R)-Methadone

Ansermot, Nicolas; Albayrak, Özgür; Schläpfer, Jürg; Crettol, Séverine; Croquette-Krokar, Marina; Bourquin, Michel; Déglon, Jean‐Jacques; Faouzi, Mohamed; Scherbaum, Norbert; Eap, Chin B.

doi:10.1001/archinternmed.2010.26

Cited by 100 publications

(57 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…hERG channel studies have shown that S-methadone is about three times more potent than the therapeutic R-enantiomer in inhibiting the repolarizing current [25,26]. Substitution of racemic methadone by R-methadone has been shown to reduce the QT interval prolongation observed with racemic methadone [27]. There are no non-clinical data on the two enantiomers of terodiline but QTc interval prolongation by racemic terodiline has been shown clinically to be exclusively due to its S-enantiomer [28].…”

Section: Overall Comments On Ich E14 Qanda Documentsmentioning

confidence: 99%

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

Shah

Morganroth²,

Kleiman³

2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

Section: Overall Comments On Ich E14 Qanda Documentsmentioning

confidence: 99%

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

Shah

Morganroth²,

Kleiman³

2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

“…On the other hand, elevated (S)-methadone causes cardiotoxicity by prolonging the QT interval and subsequently leads to torsade de pointes by blocking the voltage-gated potassium channel of the human ether-ago-go related gene (hERG) (14,15). This stereo-selective cardiotoxicity is attributed to (S)-methadone being 3.5 times more potent than (R)-methadone in blocking the hERG channel (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities

Ahmad

Sabet

Primerano

et al. 2017

Journal of Analytical Toxicology

View full text Add to dashboard Cite

Cytochrome P450 (CYP) enzyme 2B6 plays a significant role in the stereo-selective metabolism of (S)-methadone to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone metabolite. Elevated (S)-methadone can cause cardiotoxicity by prolonging the QT interval of the heart's electrical cycle. Large inter-individual variability of methadone pharmacokinetics causes discordance in the relationship between dose, plasma concentrations and side effects. The purpose of this study was to determine if one or more single nucleotide polymorphisms (SNPs) located within the CYP2B6 gene contributes to a poor metabolizer phenotype for methadone in these fatal cases. The genetic analysis was conducted on 125 Caucasian methadone-only fatalities obtained from the West Virginia and Kentucky Offices of the Chief Medical Examiner. The frequency of eight exonic and intronic SNPs (rs2279344, rs3211371, rs3745274, rs4803419, rs8192709, rs8192719, rs12721655 and rs35979566) was determined. The frequencies of SNPs rs3745274 (*9, c516G > T, Q172H), and rs8192719 (21563 C > T) were enhanced in the methadone-only group. Higher blood methadone concentrations were observed in individuals who were genotyped homozygous for SNP rs3211371 (*5, c1459C > T, R487C). These results indicate that these three CYP2B6 SNPs are associated with methadone fatalities.

show abstract

“…Blood samples for determination of R-and S-methadone plasma concentrations were taken immediately before intake of methadone on days Ϫ4, Ϫ3, Ϫ2, 2, 3, 4, 5, and 6 and on day Ϫ1 (methadone alone [reference]) and day 7 (methadone coadministered with telaprevir [test]). Blood samples were collected immediately predose and at 0.5, 1, 1.5, 2, 2.5, 3,4,5,6,8,12,16, and 24 h postdose.…”

Section: Methodsmentioning

confidence: 99%

“…Methadone is a synthetic narcotic analgesic that is administered as a combination of R-and S-isomers, with the R-isomer being mainly responsible for the opioid effect (6,7), whereas the S-isomer has been linked to prolongation of the corrected QT (QTc) (where QT represents the time between the start of the Q wave and the end of the T wave) (8). Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP).…”

mentioning

confidence: 99%

Pharmacokinetic Interaction between Telaprevir and Methadone

Heeswijk

Verboven

Vandevoorde

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

dHepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R-and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C min ), the maximum plasma concentration (C max ), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC 0 -24 ) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC 0 -24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C min values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.) H epatitis C virus (HCV) infection is widespread among previous intravenous drug users who share syringes and drug preparation equipment (1). Methadone is commonly used as a maintenance therapy for opiate dependence, and a prevalence of HCV antibody of up to 96% has been reported among patients enrolled in methadone maintenance programs (2). Telaprevir is a novel agent for the treatment of genotype 1 chronic HCV infection in adults, as shown by significantly improved rates of sustained HCV RNA clearance in combination therapy with pegylated interferon/ribavirin compared with pegylated interferon/ ribavirin alone (3-5). Use of telaprevir for treatment of HCV infection includes patients receiving methadone maintenance therapy.Methadone is a synthetic narcotic analgesic that is administered as a combination of R-and S-isomers, with the R-isomer being mainly responsible for the opioid effect (6, 7), whereas the S-isomer has been linked to prolongation of the corrected QT (QTc) (where QT represents the time between the start of the Q wave and the end of the T wave) (8). Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochro...

show abstract

Substitution of (R,S)-Methadone by (R)-Methadone

Cited by 100 publications

References 29 publications

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities

Pharmacokinetic Interaction between Telaprevir and Methadone

Contact Info

Product

Resources

About