Effects of liver disease on urinary excretion of methadone and metabolites in maintenance patients: Quantitation by direct probe chemical ionization mass spectrometry

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Abstract
This study was performed to define the amounts of methadone and metabolites excreted in urine in otherwise healthy maintenance patients, and to determine whether the metabolism and elimination of methadone, as assessed by analyses of urines, is altered in patients with liver disease. A method was developed for the simultaneous quantitation of methadone and six of its major and minor metabolites using chemical ionization mass spectrometry with direct probe introduction to increase sensitivity for analyses of the minor metabolites. Analyses of urine from unmedicated volunteers showed that the interferences at the mass range of interest (264–326) were usually small and therefore would not introduce significant error into analysis. Nineteen patients well-stabilized in chronic long-term methadone treatment were studied, five otherwise healthy males and fourteen patients with chronic liver disease (nine males and four females). Twenty-four hour urine collections were made and analyzed following extraction procedures. The concentrations of methadone and the major pyrrolidine metabolite exceeded 1μg ml−1 in all cases; the concentrations (listed in descending order) of pyrrolidone, pyrroline, hydroxymethadone, hydroxypyrroline, methadol and hydroxypyrrolidine were all less than 1 μg ml−1. The total 24 hour urinary excretion of methadone and its metabolites was 48.3% (±1.71 SEM) in otherwise healthy patients but was significantly lower, 32.6% (±3.19 SEM) in patients with liver disease (p < 0.05). The total 24 hour excretion of the pyrrolidone metabolite, the end product of two pathways of methadone metabolism, was also significantly reduced in patients with liver disease (p < 0.05). Females with liver disease had significantly higher ratios of pyrrolidine to methadone than did males with liver disease (p < 0.05).