Chiral on-line solid phase extraction coupled to liquid chromatography–tandem mass spectrometry assay for quantification of (R) and (S) enantiomers of methadone and its main metabolite in plasma

Bouquié, Regis; Hernando, Hélène; Deslandes, Guillaume; Daho, Amina Ben Mostefa; Renaud, Christian; Grall‐Bronnec, Marie; Dailly, Éric; Jolliet, Pascale

doi:10.1016/j.talanta.2014.11.052

Cited by 13 publications

(9 citation statements)

References 23 publications

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“…This assay reports improved sensitivity over any of the previously reported methods [24,33,34] with LLOQ of 0.1 µg/L per enantiomer in both matrices and LOD of 0.05 µg/L per enantiomer. Compared to the most recent report [24], optimal chromatographic separation of the enantiomers with distinctive baseline separation was achieved. Deuterated internal standards for each enantiomer were used in quantitation.…”

Section: Discussionmentioning

confidence: 77%

“…The mean concentrations of d-and l-MTD were 57.6 and 48.6 µg/L in plasma, and 64.1 and 104.3 µg/L in saliva respectively. The more recent and sensitive method [24] reports an LLOQ of 25 µg/L in plasma samples. Concentrations less than 5 µg/L were observed for both enantiomers in plasma and saliva samples.…”

Section: Applicationmentioning

confidence: 99%

“…Several hyphenated analytical methods have been proposed for the analysis of methadone enantiomers in matrices including plasma, serum, saliva, whole blood, liver microsomes and urine [24][25][26][27][28][29][30][31][32][33][34]. All of these methods were developed to assay methadone enantiomers in plasma for methadone maintenance patients or toxicological studies.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

George

Lobb

Haywood

et al. 2016

Talanta

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Methadone is a potent lipophilic synthetic opioid that is effective in the treatment of cancer pain and perceived benefit in difficult pain control scenarios (especially in cases of neuropathic pain). The use of methadone in clinical practice is challenging however, due to the narrow therapeutic window and large inter- and intra-individual variability in therapeutic response. Quantitation of the enantiomers d- and l-methadone (d- and l-MTD) in plasma and saliva provides a basis for studying its pharmacokinetics in patients with cancer and for monitoring efficacy, toxicity and side-effects. This assay involves quantitation of the enantiomers of methadone using their respective deuterated internal standards, in plasma and saliva matrices with no impact of ion suppression in either matrix. The analytical recoveries of d- and l-MTD from the saliva collection devices (Salivette®) are optimised in this novel method with an accurate and simple extraction method employing dichloromethane. Optimal enantioselective separations were achieved using an α1-acid glycoprotein chiral stationary phase and triple quadrupole tandem mass spectrometer. Linearity was demonstrated over 0.05-1000µg/L for both enantiomers in plasma and in saliva with correlation coefficients greater than 0.998. The lower limit of quantitation (LLOQ) was determined to be 0.1µg/L in plasma and saliva for d- and l-MTD. Accuracy of the method ranges from 100% to 106% even at the LLOQ and total precision, expressed as the coefficient of variation, was between 0.2% and 4.4% for both analytes in both matrices. A simple one step extraction procedure resulted in recoveries greater than 95% for both analytes, at concentrations as low as 0.5µg/L, from the Salivette®. The validated method was applied successfully in 14 paired plasma and saliva samples obtained from adult patients with cancer pain receiving methadone.

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Section: Discussionmentioning

confidence: 77%

Section: Applicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

George

Lobb

Haywood

et al. 2016

Talanta

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show abstract

“…Plasma concentrations of methadone and its (R) and (S) enantiomers were measured by liquid chromatography coupled with mass spectrometry . The analysis combined straightforward sample preparation, consisting of protein precipitation with acetonitrile and an online enrichment by a flush/back‐flush cycle before the second‐dimension chromatography.…”

Section: Methodsmentioning

confidence: 99%

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

Victorri-Vigneau

Verstuyft

Bouquié

et al. 2019

Brit J Clinical Pharma

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Aims: Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. Methods: Opioid PhArmacoLogy (OPAL) was a clinical survey of the sociodemographic characteristics, history and consequences of pathology associated with methadone maintenance treatment response and current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. Results: When comparing the three CYP2B6 genotype groups, the methadone (R)and (S)-methadone enantiomer concentrations/doses (concentrations relative to doses) were different (P = .029, P = .0019). The CYP2D6 phenotypes did not seem to be relevant with regard to methadone levels. On multivariate analysis, neither the CYP2B6 genotype nor the CYP2D6 phenotype explained the (R)-methadone concentration/dose values (P = .92; P = .86); the (S)-methadone concentration/dose values (P = .052; P = .95 [although there was a difference between the TT group and GT and GG groups {P = .019}]); or opiate cessation (P = .12; P = .90).Conclusion: The genotyping of CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

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“…The sample preparation and measurement of R/S-form enantiomeric methadone or EDDP were modified form previous articles [39,40]. In brief, sample was prepared as follows: standard (R, S) methadone or EDDP was purchased from Sigma (Sigma-Aldrich).…”

Section: Enantiomeric Eddp/methadone Detection By Lc-ms/msmentioning

confidence: 99%

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Chiang

Wang

Huang

et al. 2017

J Cellular Molecular Medi

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Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.

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Chiral on-line solid phase extraction coupled to liquid chromatography–tandem mass spectrometry assay for quantification of (R) and (S) enantiomers of methadone and its main metabolite in plasma

Cited by 13 publications

References 23 publications

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

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