PHARMACOKINETICS OF METHADONE AND ITS PRIMARY METABOLITE IN 20 OPIATE ADDICTS

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 HCl (mean 60 mg, range 10-225 mg) 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(-1) and from 5 to 55 ng . ml(-1), whereas the peak concentrations were 124-1255 ng . ml(-1) and 10-301 ng . ml(-1) for methadone and EDDP, 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(-1). kg(-1), whereas the mean elimination rate constant (beta) and plasma half-life (t(1/5)beta) were 0.026 . h(-1) (range 0.013-0.053 . h(-1)) 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.