Impact of Genetic Polymorphisms in
 ABCB1
 ,
 CYP2B6
 ,
 OPRM1
 ,
 ANKK1
 and
 DRD2
 Genes on Methadone Therapy in Han Chinese Patients

Hung, Chin‐Chuan; Chiou, Mu-Han; Huang, Bo-Hau; Hsieh, Ying‐Hen; Hsieh, Tsung-Jen; Huang, Chieh-Liang; Lane, Hsien‐Yuan

doi:10.2217/pgs.11.96

Cited by 82 publications

(99 citation statements)

References 60 publications

(51 reference statements)

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“…The interactions between CYP2C19 and CYP2B6 or CYP3A4 did not show significant associations with methadone dose (data not shown), or its dose corrected plasma R-methadone or R-EDDP concentrations both in all patients and in urine opiate test negative patients (Supplementary Tables S4 and S5). As the dose of methadone may be determined by multiple genes (Fonseca et al, 2011;Hung et al, 2011), our current results indicate that the CYP2C19 GD may play a role in the N, allelic number for SNP s and subject number for gene dose; P value, permutation test p value for SNP and Kendall's coefficient of rank correlation for gene dose; (P value): p value after removing 10 subjects who had had co-medications that influence the CYP2C19 enzymatic activity (permutation test for SNP and Kendall's coefficient of rank correlation p-value for gene dose); SD, standard deviation.…”

Section: Discussionmentioning

confidence: 99%

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

Wang

Tsou

et al. 2013

OMICS: A Journal of Integrative Biology

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Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram ( p = 0.021), and the Treatment Emergent Symptom Scale (TESS) total score ( p = 0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone ( p = 0.035), and showed a lower plasma R-methadone/ methadone dose ratio ( p = 0.007) in urine opiate test negative patients, as well as a greater QTc change ( p = 0.008) and higher total scores of TESS ( p = 0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

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Section: Discussionmentioning

confidence: 99%

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

Wang

Tsou

et al. 2013

OMICS: A Journal of Integrative Biology

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“…Clinical genetic association studies of methadone plasma concentrations are consistent with diminished methadone N-demethylation by CYP2B6.6 and liver microsomes from CYP2B6*6 carriers. In patients, methadone doses were lower (Hung et al, 2011;Levran et al, 2013), and doseadjusted steady-state S-methadone concentrations were greater (Crettol et al, 2005(Crettol et al, , 2006Eap et al, 2007;Wang et al, 2011) in CYP2B6*6 homozygotes compared with heterozygotes and noncarriers. While these observations suggested that CYP2B6 allelic variants might influence clinical methadone pharmacokinetics, only recently has this been confirmed.…”

Section: Downloaded Frommentioning

confidence: 94%

“…CYP2B6 polymorphisms may influence clinical methadone disposition. Gene-association studies suggested that the CYP2B6*6 polymorphism was associated with higher dose-adjusted steady-state plasma methadone concentrations (Crettol et al, 2005(Crettol et al, , 2006Eap et al, 2007;Wang et al, 2011) or use of lower methadone doses (Hung et al, 2011;Levran et al, 2013). Formal determination of methadone N-demethylation and clearance showed that both were greater and lesser than wild-types, respectively, in CYP2B6*4 and CYP2B6*6 carriers (Kharasch et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Differences in Methadone Metabolism by CYP2B6 Variants

2015

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Methadone is a long-acting opioid with considerable unexplained interindividual variability in clearance. Cytochrome P450 2B6 (CYP2B6) mediates clinical methadone clearance and metabolic inactivation via N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Retrospective studies suggest that individuals with the CYP2B6*6 allelic variant have higher methadone plasma concentrations. Catalytic activities of CYP2B6 variants are highly substrate-and expression-system dependent. This investigation evaluated methadone N-demethylation by expressed human CYP2B6 allelic variants in an insect cell coexpression system containing P450 reductase. Additionally, the influence of coexpressing cytochrome b 5 , whose role in metabolism can be inhibitory or stimulatory depending on the P450 isoform and substrate, on methadone metabolism, was evaluated. EDDP formation from therapeutic (0.25-1 mM) R-and S-methadone concentrations was CYP2B6.4 ‡ CYP2B6.1 ‡ CYP2B6.5 >> CYP2B6.9 CYP2B6.6, and undetectable from CYP2B6.18. Coexpression of b 5 had small and variant-specific effects at therapeutic methadone concentrations but at higher concentrations stimulated EDDP formation by CYP2B6.1, CYP2B6.4, CYP2B6.5, and CYP2B6.9 but not CYP2B6.6. In vitro intrinsic clearances were generally CYP2B6.4 ‡ CYP2B6.1 > CYP2B6.5 > CYP2B6.9 ‡ CYP2B6.6. Stereoselective methadone metabolism (S>R) was maintained with all CYP2B6 variants. These results show that methadone N-demethylation by CYP2B6.4 is greater compared with CYP2B6.1, whereas CYP2B6.9 and CYP2B6.6 (which both contain the 516G>T, Q172H polymorphism), are catalytically deficient. The presence or absence of b 5 in expression systems may explain previously reported disparate catalytic activities of CYP2B6 variants for specific substrates. Differences in methadone metabolism by CYP2B6 allelic variants provide a mechanistic understanding of pharmacogenetic variability in clinical methadone metabolism and clearance.

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“…Specifically, associations between CYP2B6*6 genotype and higher dose-adjusted steady-state plasma methadone concentrations (Crettol et al, 2005;Crettol et al, 2006;Eap et al, 2007;Wang et al, 2011), and a need for lower methadone doses (Hung et al, 2011;Levran et al, 2012) have also been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Dose-adjusted steady-state trough S-methadone concentrations were 2-fold higher in *6/*6 genotypes than in noncarriers (Crettol et al, 2005). Another investigation found that CYP2B6*6 homozygotes similarly needed lower methadone doses (Hung et al, 2011). CYP2B6*6 carriers had higher plasma S-methadone concentrations and a higher concentrationto-dose ratio for both enantiomers (Wang et al, 2011).…”

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confidence: 98%

MethadoneN-Demethylation by the CommonCYP2B6Allelic Variant CYP2B6.6

et al. 2013

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The long-acting opioid methadone displays considerable unexplained interindividual pharmacokinetic variability. Methadone metabolism clinically occurs primarily by N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), catalyzed predominantly by CYP2B6. Retrospective studies suggest that the common allele variant CYP2B6*6 may influence methadone plasma concentrations. The catalytic activity of CYP2B6.6, encoded by CYP2B6*6, is highly substrate-dependent. This investigation compared methadone Ndemethylation by CYP2B6.6 with that by wild-type CYP2B6.1. Methadone enantiomer and racemate N-demethylation by recombinant-expressed CYP2B6.6 and CYP2B6.1 was determined. At substrate concentrations (0.25-2 mM) approximating plasma concentrations occurring clinically, rates of methadone enantiomer N-demethylation by CYP2B6.6, incubated individually or as the racemate, were one-third to one-fourth those by CYP2B6.1. For methadone individual enantiomers and metabolism by CYP2B6.6 compared with CYP2B6.1, V max was diminished, K s was greater and the in vitro intrinsic clearance was diminished 5-to 6-fold. The intrinsic clearance for R-and S-EDDP formation from racemic methadone was diminished approximately 6-fold and 3-fold for Rand S-methadone, respectively. Both CYP2B6.6 and CYP2B6.1 showed similar stereoselectivity (S>R-methadone). Human liver microsomes with diminished CYP2B6 content due to a CYP2B6*6 allele had lower rates of methadone N-demethylation. Results show that methadone N-demethylation catalyzed by CYP2B6.6, the CYP2B6 variant encoded by the CYP2B6*6 polymorphism, is catalytically deficient compared with wild-type CYP2B6.1. Diminished methadone N-demethylation by CYP2B6.6 may provide a mechanistic explanation for clinical observations of altered methadone disposition in individuals carrying the CYP2B6*6 polymorphism.

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Impact of Genetic Polymorphisms in ABCB1 , CYP2B6 , OPRM1 , ANKK1 and DRD2 Genes on Methadone Therapy in Han Chinese Patients

Abstract: These findings provide new insight to the fact that the interindividual variability of methadone dosage requirement is polygenetic and cannot be explained by a single-gene effect.

Cited by 82 publications

References 60 publications

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

Differences in Methadone Metabolism by CYP2B6 Variants

MethadoneN-Demethylation by the CommonCYP2B6Allelic Variant CYP2B6.6

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