The disposition of methadone was studied in eight opiate dependent subjects during detoxification. Plasma concentrations were determined by mass fragmentography of 48 hours after administration of methadone 20 mg as tablets and simultaneous intravenous injection of deuterium-labelled methadone 20 mg. Pharmacokinetic parameters were calculated for the intravenous dose assuming a two compartment of open model. Bioavailability was determined by comprising the areas under the plasma concentration versus time curves of unlabelled and labelled methadone. The beta-phase plasma half-lives varied five-fold, with a range from 8.5 to 47 h. The apparent volumes of distribution varied from 2.1 to 5.6 l/kg. Five patients had a bioavailability exceeding 90%, and three had lower bioavailabilities of between 41 and 76%. The unlabelled and labelled drug appeared to be pharmacokinetically equivalent. The data show that for a majority of these subjects the bioavailability was higher than 45%, the previously reported value. The marked individual variation in methadone pharmacodynamics and kinetics, and the possibilities both of cellular and metabolic tolerance, require an individually optimized dosage regimen.

The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH approximately 5.2) and in the other the urine was made alkaline (pH approximately 7.8) by treatment with sodium hydrogen carbonate. d, l-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the beta-phase were 19.5 +/- 3.6 h (acidic urine) and 42.1 +/- 8.8h (alkaline urine), respectively (p less than 0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51 +/- 0.41 l/kg to 5.24 +/- 0.83 l/kg (p less than 0.01). The body clearance decreased from 134 +/- 21 ml/min (acidic) to 91.9 +/- 9.1 ml/min (alkaline urine) (p less than 0.01). The ration M plasma/M RBC was about 2.3 and the elimination of M from RBCs was good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio M saliva/ M plasma (0.26-2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.

Studies with single doses of methadone have shown that the oral biological availability is 79±21%, range 41–99%. The rate of elimination is mostly due to metabolic clearance. Below a urinary pH of 6, renal clearance becomes of quantitative importance. In five subjects treated with ammonium chloride (acidic urine), the plasma half‐life of methadone was found to be 19.5±3.6 h. When treated with sodium bicarbonate the same subjects had plasma half‐lives of 42.1±8.8 h. During continuous treatment with methadone, cellular tolerance may occur and in some subjects also metabolic tolerance. In treatment of severe cancer pain such adaptive changes in methadone pharmacodynamics and pharmacokinetics are best managed by a regimen involving a fixed dose but a flexible and patient‐controlled dosage interval.

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