Role of CYP2B6 in Stereoselective Human Methadone Metabolism

Totah, Rheem A.; Sheffels, Pamela; Roberts, T. Grady; Whittington, Dale; Thummel, Kenneth E.; Kharasch, Evan D.

doi:10.1097/aln.0b013e3181642938

Cited by 171 publications

(188 citation statements)

References 44 publications

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“…Methadone clearance was doubled by efavirenz and rifampin, which induce CYP2B6, as well as CYP3A4, and by ritonavir, which induces CYP2B6 while inhibiting CYP3A (Kharasch et al, 2004a(Kharasch et al, , 2008a. Increasing the activity of CYP2B6, which metabolizes methadone stereoselectively (Gerber et al, 2004;Kharasch et al, 2004a;Totah et al, 2007Totah et al, , 2008Chang et al, 2011), increased plasma R/S methadone ratios (Kharasch et al, 2004a(Kharasch et al, , 2008a(Kharasch et al, ,c, 2012bTotah et al, 2008), whereas inhibiting CYP3A, which metabolizes methadone nonstereoselectively, did not (Kharasch et al, 2009a(Kharasch et al, ,b, 2012a. CYP2B6 inhibition by ticlopidine increased methadone enantiomers AUC and reduced methadone N-demethylation and clearance (Kharasch and Stubbert, 2013).…”

Section: Controlmentioning

confidence: 95%

“…CYP2B6 catalyzes methadone N-demethylation in vitro as avidly as CYP3A4 and CYP2B6 but not CYP3A4 is stereoselective (Gerber et al, 2004;Kharasch et al, 2004a;Totah et al, 2007Totah et al, , 2008Chang et al, 2011). Methadone clearance was doubled by efavirenz and rifampin, which induce CYP2B6, as well as CYP3A4, and by ritonavir, which induces CYP2B6 while inhibiting CYP3A (Kharasch et al, 2004a(Kharasch et al, , 2008a.…”

Section: Controlmentioning

confidence: 99%

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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%

Section: Controlmentioning

confidence: 99%

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

Kharasch

Stubbert

2013

Drug Metab Dispos

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“…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%

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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“…The goal of predictable and reproducible effective dosing is confounded by considerable interindividual variability in methadone pharmacokinetics, particularly in its clearance (up to 100-fold) (Totah et al, 2008). This variability is further complicated by stereoselectivity in methadone pharmacokinetics.…”

mentioning

confidence: 99%

“…Although potential interactions with methadone via CYP3A and CYP2B6 have been carefully studied in vitro (Iribarne et al, 1997;Foster et al, 1999;Wang and DeVane, 2003;Kharasch et al, 2004) and in vivo (Eap et al, 2002;Totah et al, 2008), it is clear that these enzymes cannot fully explain variability in methadone pharmacokinetics. Other potential routes of metabolism may be important.…”

mentioning

confidence: 99%

Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)

Bies²,

Kamden

et al. 2010

Drug Metab Dispos

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ABSTRACT:The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the K m (4 M). To test for mechanismbased inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1-1000 M), R-or Smethadone (0.5-500 M), or EDDP or EMDP (10 and 100 M) followed by incubation with testosterone at a V max concentration (50 M). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time-and concentrationdependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The K I and k inact values for racemic methadone were calculated to be 40.6 ؎ 2.8 M and 0.061 ؎ 0.001 min ؊1, respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients.

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Role of CYP2B6 in Stereoselective Human Methadone Metabolism

Abstract: These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition.

Cited by 171 publications

References 44 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

Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)

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