CYP2B6 Polymorphisms Influence the Plasma Concentration and Clearance of the Methadone S-Enantiomer

Wang, Sheng-Chang; Ho, Ing-Kang; Tsou, Hsiao-Hui; Tian, Jia-Ni; Hsiao, Chin‐Fu; Chen, Chia‐Hui; Tan, Happy Kuy‐Lok; Lin, Linen; Wu, Chen; Su, Lien-Wen; Huang, Chieh-Liang; Yang, Yi-Hong; Liu, Ming-Lun; Lin, Keh‐Ming; Chen, Chun-Yu; Liu, Shu Chih; Wu, Hsiao-Yu; Chan, Hsiu‐Wen; Tsai, Ming-Hsien; Lin, Pin‐Yao; Liu, Yuli

doi:10.1097/jcp.0b013e318222b5dd

Cited by 68 publications

(66 citation statements)

References 26 publications

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“…CYP2B6 inhibition by ticlopidine increased methadone enantiomers AUC and reduced methadone N-demethylation and clearance (Kharasch and Stubbert, 2013). Pharmacogenetic studies also evidence CYP2B6 involvement in methadone disposition, with CYP2B6*6/*6 homozygotes having higher dose-adjusted S-methadone plasma concentrations and/or lower dose requirements than heterozygotes or noncarriers (Crettol et al, 2006;Wang et al, 2011;Levran et al, 2013).…”

Section: Controlmentioning

confidence: 95%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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Section: Controlmentioning

confidence: 95%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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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: 99%

“…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%

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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CYP2B6 Polymorphisms Influence the Plasma Concentration and Clearance of the Methadone S-Enantiomer

Cited by 68 publications

References 26 publications

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Differences in Methadone Metabolism by CYP2B6 Variants

MethadoneN-Demethylation by the CommonCYP2B6Allelic Variant CYP2B6.6

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