Methadone<i>N</i>-Demethylation by the Common<i>CYP2B6</i>Allelic Variant CYP2B6.6

Gadel, Sarah; Crafford, Amanda; Regina, Karen J.; Kharasch, Evan D.

doi:10.1124/dmd.112.050625

Cited by 42 publications

(59 citation statements)

References 38 publications

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“…3). There was evidence for substrate or product inhibition at the highest concentration of S-methadone (but not R-methadone), as observed previously (Gadel et al, 2013). Eadie-Hosfstee plots were generally linear, with or without coexpressed b 5 (not shown).…”

Section: Resultssupporting

confidence: 77%

“…Methadone Metabolism. Incubations (200 ml) with R-or S-methadone were performed as previously described (Gadel et al, 2013), with minor modifications. Preliminary experiments showed that N-demethylation was linear for up to 45 minutes; routine incubations were 10 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…EDDP formation by CYP2B6 variants was compared by analysis of variance. EDDP formation versus substrate concentration data were analyzed by nonlinear regression analysis (SigmaPlot 12.5; Systat, San Jose, CA) evaluating a single-enzyme Michaelis-Menten, AdairPauling, or substrate (or product inhibition) model as described previously (Totah et al, 2007(Totah et al, , 2008Gadel et al, 2013). The choice of model was based on whether the Eadie-Hofstee plots were linear or nonlinear and the goodness of fit regression diagnostics.…”

Section: Methodsmentioning

confidence: 99%

“…Both methadone clearance and N-demethylation are stereoselective. Methadone N-demethylation in vitro, by human liver microsomes and by expressed cytochrome P450s (P450s), is catalyzed most efficiently by CYP2B6 and CYP3A4, and only CYP2B6 N-demethylates methadone stereoselectively (S.R) (Gerber et al, 2004;Kharasch et al, 2004;Totah et al, 2007Totah et al, , 2008Chang et al, 2011;Gadel et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The CYP2B6*6 allele is of particular interest, owing to its frequent occurrence (particularly in African, Asian, and Hispanic populations) and therapeutic significance for the metabolism, pharmacokinetics, and clinical effects of efavirenz, cyclophosphamide, and bupropion (Turpeinen and Zanger, 2012;Zanger and Klein, 2013). We recently reported that methadone Ndemethylation catalyzed by CYP2B6.6, the CYP2B6 variant encoded by the CYP2B6*6 polymorphism, is catalytically deficient compared with wild-type CYP2B6.1, and that human liver microsomes with diminished CYP2B6 content owing to a CYP2B6*6 allele had lower rates of methadone N-demethylation (Gadel et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differences in Methadone Metabolism by CYP2B6 Variants

2015

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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Factors Affecting Drug Metabolism

2020

Human Drug Metabolism

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MethadoneN-Demethylation by the CommonCYP2B6Allelic Variant CYP2B6.6

Cited by 42 publications

References 38 publications

Differences in Methadone Metabolism by CYP2B6 Variants

Differences in Methadone Metabolism by CYP2B6 Variants

Principles of Drug Metabolism

Factors Affecting Drug Metabolism

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