Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment

Kringen, Marianne Kristiansen; Chalabianloo, Fatemeh; Bernard, Jean‐Paul; Bramness, Jørgen G.; Molden, Espen; Høiseth, Gudrun

doi:10.1097/ftd.0000000000000437

Cited by 33 publications

(40 citation statements)

References 28 publications

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“…28 Methadone exposure is significantly higher in subjects homozygous for CYP2B6*6. 29 The allele frequency of CYP2B6*6 is relatively high as follows: 33% to 50% in blacks, 10% to 21% in Asians, 14% to 27% in whites, and 62% in Papua New Guineans. 28 Therefore, enrolling subjects with CYP2B6*6 polymorphism may mask the effect of perpetrator medication(s) on methadone and bias the study results.…”

Section: Discussionmentioning

confidence: 99%

“…The CYP2B6 gene is highly polymorphic, and the most common and clinically significant variant allele is CYP2B6*6 with markedly reduced hepatic expression and activity . Methadone exposure is significantly higher in subjects homozygous for CYP2B6*6 . The allele frequency of CYP2B6*6 is relatively high as follows: 33% to 50% in blacks, 10% to 21% in Asians, 14% to 27% in whites, and 62% in Papua New Guineans .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Drug‐Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned

Younis

Lakota

Volpe

et al. 2019

The Journal of Clinical Pharma

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Different views appear in the literature on the extent of specific cytochrome P450 (CYP) involvement in methadone metabolism. The aim of this work is to leverage knowledge from drug-drug interaction (DDI) studies in new drug applications between methadone and antiviral medications to better understand methadone disposition and to inform design of future DDI studies with methadone. A database of DDI studies between all FDA-approved human immunodeficiency virus and hepatitis C virus medications and methadone was constructed. The database contains data from 29 DDI studies. Sixteen of the 29 studies had statistically significant changes in methadone area under the concentration-time curve. Methadone exposure was either decreased or unchanged when it was coadministered with weak to strong CYP3A inhibitors or a moderate CYP3A4 inducer. Methadone exposure was reduced when it was coadministered with CYP2B6 inducers. The role of other enzymes (CYP2C9, CYP2C19, and CYP2D6) cannot be fully elucidated from these studies. In conclusion, CYP2B6 plays a prominent role in methadone metabolism, although methadone exposure is not sensitive to CYP3A perturbation. In designing methadone DDI studies, (1) measuring R-and S-methadone is more informative than measuring total methadone, and (2) CYP2B6 genotyping of subjects enrolled in methadone DDI studies should be considered. Finally, there is a need for the development of predictive models to determine the influence of medications on methadone disposition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Drug‐Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned

Younis

Lakota

Volpe

et al. 2019

The Journal of Clinical Pharma

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“…The haplotype with reduced enzyme function is CYP2B6*6 (two polymorphisms) with a frequency ranging between 10 and 50% . Patients homozygous for CYP2B6*6 showed a > 90% higher d , l ‐methadone concentration‐to‐dose ratio, although CYP2B6 genotype groups showed considerable overlap suggesting the involvement of other factors …”

Section: Clinical Pharmacology Of Dl‐methadonementioning

confidence: 99%

“…[70][71][72] Patients homozygous for CYP2B6*6 showed a > 90% higher D,L-methadone concentration-to-dose ratio, although CYP2B6 genotype groups showed considerable overlap suggesting the involvement of other factors. 73 Besides achievable plasma levels, concentrations in the central nervous system are of special interest given the claimed efficacy of D,L-methadone against brain tumors. A comprehensive analysis of 48 forensic cases revealed very low unbound D,L-methadone concentrations in the forebrain samples.…”

Section: Dl-methadone Against Cancer Painmentioning

confidence: 99%

Methadone against cancer: Lost in translation

Theile

Mikus

2018

Intl Journal of Cancer

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Recently, the opioid analgesic d,l-methadone has gained much attention as a potential antineoplastic compound, considerably triggered through lay press and media. In consequence, physicians and pharmacists are currently confronted with numerous patients willing to use d,l-methadone against their malignancies. Well-performed in vitro and in vivo models have in fact shown pro-apoptotic effects of d,l-methadone or other opioids, but also proliferation-stimulating properties. Moreover, the mechanisms of proposed opioid-stimulated apoptosis are incompletely described or contradicting. Finally, the receptors mostly responsible for induction of apoptosis by d,l-methadone remain unclear as contributions of both µ-opioid receptors, Fas cell death receptors, toll-like receptors, N-Methyl-d-aspartate receptors and opioid growth factor receptors were suggested. Such ambiguity prevents rational application of d,l-methadone or patient stratification to enhance beneficial antineoplastic effects. From a clinical point of view, d,l-methadone and other opioids might in fact prolong survival, but such effects likely originate from their analgesic and neuro-psychotropic properties and, thus, improvements of quality of life. Crucial obstacles to the administration of d,l-methadone are incomplete knowledge about its systemic disposition, highly variable pharmacokinetics, profound drug-drug- or drug-disease interaction and QT-prolongation potential. This article summarizes and rates the pharmacological basis of d,l-methadone as an antineoplastic agent and puts its administration in clinical oncology into perspective. Despite enthralling experimental findings about d,l-methadone-mediated apoptosis in cancerous cells or tissues, clinicians should realize the current lack of evidence for the use of d,l-methadone as an antineoplastic agent. Its administration against cancer pain is, however, tenable, albeit restricted to certain clinical situations.

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“…Methadone is intensively metabolized by the liver and intestines. Various in vitro and in vivo studies have shown the involvement of different cytochrome P450 (CYP) enzymes, particularly CYP2B6, in methadone metabolism, associated with the CYP2B6‐G516T genetic polymorphism and, to a lesser extent, CYP2D6, CYP3A4, and the gene encoding ATP Binding Cassette Subfamily B Member 1 ( ABCB1 , the permeability glycoprotein [P‐gp] transporter) . The influence of genetic polymorphisms on pharmacodynamic properties and treatment response has been less explored, and is not supported by much evidence .…”

Section: Introductionmentioning

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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Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment

Abstract: Patients homozygous for CYP2B6*6 had a >90% higher methadone C/D ratio. Genotyping of CYP2B6 may therefore be of value when assessing dose requirements in methadone maintenance treatment.

Cited by 33 publications

References 28 publications

Drug‐Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned

Drug‐Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned

Methadone against cancer: Lost in translation

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

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