Disposition of methadone in methadone maintenance

Änggård, Erik; Gunne, Lars M.; Holmstrand, J; McMahon, Robert E.; Sandberg, Carl-Gustaf; Sullivan, Hugh R.

doi:10.1002/cpt1975173258

Cited by 85 publications

(32 citation statements)

References 5 publications

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“…Methadone is metabolized in the liver by the cytochrome P450 system and, more specifically, by the CYP3A4 isoform, which is involved in the metabolism of over 50% of the medical agents [33] . The wide interindividual variability [34][35][36] recorded, and the fact that CYP3A4 can be induced by several active principles [37] , may explain why a number of patients are undermedicated if a standard dose of methadone is used.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcomes of Treatment-Resistant Heroin Addicts with and without DSM-IV Axis 1 Psychiatric Comorbidity (Dual Diagnosis)

Maremmani

Pacini²,

Lubrano³

et al. 2008

Eur Addict Res

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Objective: The aim of this study was to compare the long-term outcomes of treatment-resistant heroin addicts with and without DSM-IV axis I psychiatric comorbidity (dual diagnosis). Method: 129 heroin addicts who also met criteria for treatment resistance, 66 with one or more DSM-IV axis I psychiatric diagnosis (DD patients), and 63 without DSM-IV axis I psychiatric comorbidity (NDD patients) were monitored prospectively (6 years on average, min. 1, max. 9) along a methadone maintenance treatment program (MMTP). Results: The rates for survival-in-treatment were about 50% for NDD patients and about 70% for DD patients. After 4 years of treatment onwards, such rates tended to become stable. DD patients showed better outcome measures than NDD patients. A significantly higher methadone dose was needed to have DD patients stabilized. Conclusions: Contrary to expectations, treatment-resistant patients with psychiatric comorbidity showed a better long-term outcome than treatment-resistant patients without psychiatric comorbidity.

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Section: Discussionmentioning

confidence: 99%

Long-Term Outcomes of Treatment-Resistant Heroin Addicts with and without DSM-IV Axis 1 Psychiatric Comorbidity (Dual Diagnosis)

Maremmani

Pacini²,

Lubrano³

et al. 2008

Eur Addict Res

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“…1 (Sporkert and Pragst, 2000). 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).…”

Section: Introductionmentioning

confidence: 91%

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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“…Further investigations should also be enzyme induction and other adaptive changes on the metabolism of methadone [25,28,36,49,50]. Whether aimed at clarifying the roles of plasma binding and enantioselective kinetics [48], and the influence of autothese complexities present formidable obstacles to the 4 From population analysis with t 1/2,z as a primary parameter with a log-normal distribution staff of the Leeds Addiction Unit for their assistance.…”

Section: Pharmacokineticsmentioning

confidence: 99%

The pharmacokinetics of methadone in healthy subjects and opiate users

Wolff¹,

Rostami‐Hodjegan

Shires

et al. 1997

Brit J Clinical Pharma

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Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

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Disposition of methadone in methadone maintenance

Cited by 85 publications

References 5 publications

Long-Term Outcomes of Treatment-Resistant Heroin Addicts with and without DSM-IV Axis 1 Psychiatric Comorbidity (Dual Diagnosis)

Long-Term Outcomes of Treatment-Resistant Heroin Addicts with and without DSM-IV Axis 1 Psychiatric Comorbidity (Dual Diagnosis)

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

The pharmacokinetics of methadone in healthy subjects and opiate users

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