Interaction of methadone with substrates of human hepatic cytochrome P450 3A4

Iribarne, Christelle; Dréano, Yvonne; Bardou, L.; Ménez, J. F.; Berthou, F.

doi:10.1016/s0300-483x(96)03549-4

Cited by 83 publications

(56 citation statements)

References 22 publications

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“…P450-mediated p-hydroxylation of one of the aromatic rings has also been reported (Sullivan and Due, 1973;Anggård et al, 1975;Foster et al, 1999). Initial in vitro data suggested that CYP3A4 is the major isoform responsible for the in vivo clearance of methadone in humans (Iribarne et al, 1996;Iribarne et al, 1997). However, recent clinical data have challenged the major role of CYP3A4 in methadone metabolism (Kharasch et al, 2009).…”

Section: Introductionmentioning

confidence: 92%

Mechanism-Based Inactivation of Cytochrome P450 2B6 by Methadone through Destruction of Prosthetic Heme

2012

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ABSTRACT:Methadone is a -opioid receptor agonist widely used in the treatment of narcotic addiction and chronic pain conditions. Methadone is metabolized predominantly in the liver by cytochromes P450 to its pharmacologically inactive primary metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. Initial in vitro data suggested that CYP3A4 is the major isoform responsible for the in vivo clearance of methadone in humans. However, recent clinical data have indicated that CYP2B6 is actually the major isoform responsible for methadone metabolism and clearance in vivo. In this study, methadone was shown to act as a mechanism-based inactivator of CYP2B6. Methadone inactivates CYP2B6 in a time-, concentration-, and NADPH-dependent manner with a K I ‫؍‬ 10.0 M and k inact ‫؍‬ 0.027 min ؊1. The loss of CYP2B6 activity in the presence of methadone and NADPH occurred with concomitant loss of the reduced CO spectrum of the P450. Moreover, there was good correlation between the loss of CYP2B6 activity and the loss of the CO-binding spectrum. High-performance liquid chromatography analysis of the native heme of the inactivated CYP2B6 demonstrated that approximately 75% loss of heme was accompanied by comparable inactivation of CYP2B6. Liquid chromatography-mass spectrometry analysis did not reveal the formation of a protein adduct during the inactivation. The evidence strongly suggests that destruction of prosthetic heme is the underlying mechanism leading to the inactivation of CYP2B6 by methadone.

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Section: Introductionmentioning

confidence: 92%

Mechanism-Based Inactivation of Cytochrome P450 2B6 by Methadone through Destruction of Prosthetic Heme

2012

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“…The pharmacokinetics of opioids is known to be affected by pregnancy, as well as by the co-administration of certain other substances that interfere with cytochrome P 450 -induced metabolism [33,34] . Under such circumstances, use of twice-daily slow-release morphine may be necessary, but then take-home dosing may not be feasible.…”

Section: Discussionmentioning

confidence: 99%

Use of Slow-Release Oral Morphine for the Treatment of Opioid Dependence

Kraigher¹,

Jagsch

Gombas

et al. 2005

Eur Addict Res

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Aims: In addition to methadone, other synthetic opioids are now available for the treatment of opioid dependence. The study investigated the treatment satisfaction of oral slow-release morphine for maintenance therapy in opioid-dependent patients in an open-label 3-week study. Design: We evaluated the treatment satisfaction of oral slow-release morphine hydrochloride for 3 weeks in 110 patients meeting the diagnosis of opioid dependence (DSM-IV 304.0) or polysubstance dependence (DSM-IV 304.9). Measurements: Primary outcome measures were the study retention rate, urinalysis for additional illicit consumption other than heroin, cravings and withdrawal symptoms 24 h after the last intake of the medication (duration of action of treatment). Findings: In total, 103 patients completed the study, representing a retention rate of 94%. Patients reported significant improvements in somatic complaints, as well as significant reductions in heroin and cocaine cravings (p < 0.0001) and in additional consumption of cocaine in supervised urinalysis (p = 0.0083). Additional illicit consumption of benzodiazepines remained unchanged. Conclusions: The high study retention rate implies a good acceptance of slow-release acting oral morphine. However, randomised, double-blind, double-dummy studies with a longer investigational period are needed to meet criteria for evidence-based medicine.

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“…Oral morphine and hydromorphone are primarily metabolized in the liver through the uridine-diphosphoglucuronosyltransferase (UGT) system [68]. Fentanyl [69] and methadone [70] are metabolized by the CYP3A4 enzyme, which is responsible for the complete or partial metabolism of 50% of all known drugs. Genetic variation in CYP2D6 results in poor metabolism of the opioid codeine to its active metabolite morphine [66,71].…”

Section: Opioid Metabolismmentioning

confidence: 99%

Clinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

Ross¹,

Riley²,

Quigley³

et al. 2006

The Oncologist

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Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. Since a third of the population will die from cancer, and of these, 80% will experience severe pain in their final year of life, effective treatment of cancer-related pain remains both a high priority and an ongoing challenge in clinical practice. Individuals with moderate to severe cancer-related pain require treatment with strong analgesics, namely opioids.There is evidence to support the therapeutic maneuver of opioid switching in clinical practice, but further evidence is needed to elucidate the underlying mechanisms for interindividual differences in response to different opioids. Large, robust clinical trials will be needed if clinical differences among side-effect profiles of different opioids are to be clearly demonstrated. This review discusses candidate genes, which contribute to opioid response; many other genes have also been implicated in "pain" from animal or human studies. In order to continue to evaluate the genetic contributions to both pain susceptibility and analgesic response, further candidate genes need to be considered. Good pain control remains a high priority for clinicians and patients, and there is much work to be done to further individualize analgesic therapy for patients with cancer.

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Interaction of methadone with substrates of human hepatic cytochrome P450 3A4

Cited by 83 publications

References 22 publications

Mechanism-Based Inactivation of Cytochrome P450 2B6 by Methadone through Destruction of Prosthetic Heme

Mechanism-Based Inactivation of Cytochrome P450 2B6 by Methadone through Destruction of Prosthetic Heme

Use of Slow-Release Oral Morphine for the Treatment of Opioid Dependence

Clinical Pharmacology and Pharmacotherapy of Opioid Switching in Cancer Patients

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