Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone

Kharasch, Evan D.; Hoffer, Christine; Whittington, Dale; Sheffels, Pamela

doi:10.1016/j.clpt.2004.05.003

Cited by 217 publications

(295 citation statements)

References 64 publications

(119 reference statements)

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“…and oral methadone (Kharasch et al, 2004a(Kharasch et al, , 2008a(Kharasch et al, , 2009a(Kharasch et al, ,b, 2012a. Subjects received i.v.…”

Section: Methodsmentioning

confidence: 99%

“…ondansetron followed 30 minutes later by i.v. racemic unlabeled (d0)-methadone HCl (6.0 mg, equivalent to 5.4 mg free base) and oral deuterated racemic (d5)-methadone HCl (11.0 mg, equivalent to 9.86 mg free base, with 100 ml of water, synthesized and used under Investigational New Drug approval (Kharasch et al, 2004a). Subjects received a standard breakfast and lunch 2 and 4 hours after methadone, respectively, and free access to food and water thereafter.…”

Section: Methodsmentioning

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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“…and oral methadone (Kharasch et al, 2004a(Kharasch et al, , 2008a(Kharasch et al, , 2009a(Kharasch et al, ,b, 2012a. Subjects received i.v.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Kharasch

Stubbert

2013

Drug Metab Dispos

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“…19 There is a tremendous inter-individual variability in cytochrome P450 activity and this variation can be attributed to genetic polymorphism as well as the profound alterations due to certain medications (Table II).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Review article: Perioperative pain management of patients on methadone therapy

Peng

Tumber

Gourlay

2005

Can J Anesth/J Can Anesth

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P Pu ur rp po os se e: : Methadone, an opioid traditionally associated with the management of opioid addictive disorders, has been prescribed increasingly as an analgesic for the management of various chronic pain conditions. Despite the increasing popularity of methadone, most anesthesiologists are not familiar with its complex pharmacology. The purpose of this article is to review the pharmacology of methadone and to suggest a management algorithm for the perioperative care of methadone patients.S So ou ur rc ce e: : A Medline search was performed to obtain the published literature on the pharmacology of methadone and its use perioperatively.P Pr ri in nc ci ip pa al l f fi in nd di in ng gs s: : The complexity of methadone's pharmacology is characterized by a high inter-individual variability, a potential for interaction with other medications, and a long elimination half-life. The postoperative management of methadone patients may be difficult as they are often 'opioid-tolerant' but may be 'pain-intolerant'. For those patients who are taking part in methadone-maintenance programs, there is a potential for the problematic use of opioids or other substances. The management plan for patients taking methadone may differ depending on the type of surgery and the associated perioperative differences in fasting status and gastrointestinal function. In consideration of all the factors listed above, a management algorithm is outlined for the perioperative care of methadone patients.C Co on nc cl lu us si io on n: : Methadone is an opioid with complex properties, and a patient that is taking methadone can represent a unique challenge to the anesthesiologist. A good understanding of the pharmacology of methadone and of the type of patients on this medication will help to improve their perioperative care. Objectif

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“…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 hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone

Cited by 217 publications

References 64 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

Review article: Perioperative pain management of patients on methadone therapy

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

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