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·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 (β) and plasma half-life (t_1/2β) 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.