Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

Abstract

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 x ml(-1) and from 5 to 55 ng x ml(-1), whereas the peak concentrations were 124-1255 ng x ml(-1) and 10-301 ng x ml(-1) 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 x min(-1) x kg(-1), whereas the mean elimination rate constant (beta) and plasma half-life (t1/2beta) were 0.026 x h(-1) (range 0.013-0.053 x 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.