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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The clinical effectiveness of l-methadone maintenance treatment (LMMT) carried out using d,l-methadone or l-methadone have been compared with ambulatory heroin-dependent subjects. A total of 40 heroin-dependent subjects, previously maintained on l-methadone in Frankfurt am Main, were divided into two groups under randomised double-blind conditions and received either an equivalent dose of l-methadone as d,l-methadone or remained on the previous l-methadone treatment. Requests for a change in the dose of d,l-methadone and l-methadone were recorded, urine samples for determination of illicit drug use were collected and the individual level of opiate craving was determined over a 22-day observation period. There was no significant difference between the two groups in the number requests for a dose change (dose increase <10%). However, there was a significant increase in heroin use in the group which continued to receive l-methadone. Although there was less variability in opiate craving in the group receiving d,l-methadone, the mean intensity of opiate craving did not differ between the two groups. The mean l-methadone dose:l-methadone plasma concentration ratio, an index of the bioavailability of l-methadone in individual subjects, showed no significant change when the treatment was changed to d,l-methadone. The mean d-methadone:l-methadone plasma concentration ratio was 1.17. There was no significant difference between these ratios for day 15 and day 22. The mean l-methadone:EDDP plasma concentration ratio in the l-methadone group was 22.2 and the d,l-methadone:EDDP plasma concentration ratio was 18.4 . The plasma EDDP concentration in the d,l-methadone group increased 3-fold after starting treatment with d,l-methadone. These findings suggest that d,l-methadone can be used in methadone maintenance treatment of heroin-dependent subjects but that further studies are required to evaluate pharmacokinetic interactions between methadone enantiomers.

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