Urinary metabolites of DL-methadone in maintenance subjects

Sullivan, Hugh R.; Due, Susan L.

doi:10.1021/jm00266a009

Cited by 98 publications

(48 citation statements)

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“…Although in early studies using animal models no analgesic activity for EDDP has been found [21,23], it might be premature to exclude any psychopharmacological activity for EDDR Considering the continuous presence of EDDP in long-term methadone addicts and the close chemical resemblance with methadone, it would be worthwhile submitting EDDP to further pharmacodynamic investigations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

Vos

Geerlings

Brink³

et al. 1995

Eur J Clin Pharmacol

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In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HC1 (mean 60 rag, range 10-225 rag) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65-630 ng'ml -~ and from 5 to 55 ng'm1-1, whereas the peak concentrations were 124-1255 ng.m1-1 and 10 301 ng'ml -~ for methadone and EDDR respectively. The calculated ratios between the area under the curve (AUC(0_24 h)) for methadone and the AUC(0_24 h) for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml.min-l.kg -~, whereas the mean elimination rate constant (/~) and plasma half-life (t,/fi) were 0.026'h -1 (range 0.013-0.053"h -~) and 31.2 h (range 13-53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.Since methadone maintenance therapy (MMT) was introduced [1], many studies have been conducted to establish the pharmacokinetics of methadone. Unfortunately they have not led to a general consensus with regard to well-defined dosage schedules related to clinical and therapeutic efficacy. This might be explained in part by the very divergent results of most of the studies performed so far. For example, plasma half-lives of methadone in tolerant subjects under MMT have varied from 19 h [2] to even 75 h [3]. Both studies were performed in closed metabolic wards. The same variability has applied for bioavailability, which has ranged from 36% to 106% (mean 87%) among 12 tolerant opiate addicts [4], also in a closed metabolic ward. Another study revealed a mean bioavailability of 79% (range 41-99%) [5]. Furthermore, there has been no consensus as to whether the disposition of methadone follows a one-[6-8] or a two- [4,5,9] compartment model. However, most of these studies were performed under divergent, hardly comparable circumstances. The pharmacokinetics in non-tolerant ("naive") subjects might differ from those in tolerant subjects [10,11]. Also short-term treatment might give different results from long-term (steady-state) treatment [12,13]. However, it seems that determinations of plasma methadone in outdoor addicts show wider scatters in elimination half-lifes than those performed in closed metabolic wards: 17.8-63.8 h [8] and 18.9-43 h [2], respectively.The metabolism of methadone has been studied intensively. Many metabolites have been traced and identified in human urine [14,15]. Nevertheless essential knowledge about the formation and disposition of the major metabolite of methadone, EDDP (1,5-dimethyl-3,3-diphenyl-2-eth...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

Vos

Geerlings

Brink³

et al. 1995

Eur J Clin Pharmacol

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“…It is intensively metabolized in the body, mainly at the level of the liver by the cytochrome P450 (CYP) 3A4, CYP2B6, and to a lesser extent by CYP2D6 [2] . Its main metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), is inactive [3] . LAAM is successively N-demethylated, mainly by CYP3A4, CYP2B6 and CYP2C18 to L -␣ -acetylnormethadol and L -␣ -acetyldinormethadol [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

In vitro P-Glycoprotein-Mediated Transport of (R)-, (S)-, (R,S)-Methadone, LAAM and Their Main Metabolites

et al. 2007

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Methadone and L-α-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.

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“…The clinically used Rac-methadone is a mixture of (R)-and (S)-enantiomers in which the (R)-methadone is the major pharmacologically active form. In humans, a major metabolite of methadone is 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), which is pharmacologically inactive (Sullivan and Due 1973). The major active binding sites of methadone are the CNS m and d opioid receptors.…”

Section: Introductionmentioning

confidence: 99%