Effect of urinary pH on the disposition of methadone in man

Abstract

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.

Comparison of Cannabinoid Concentrations in Plasma, Oral Fluid and Urine in Occasional Cannabis Smokers After Smoking Cannabis Cigarette

“…Indeed, the importance of pH has been shown previously on the pharmacokinetics of methadone for example [43,44]. Earlier studies have indicated that an increase in methadone excretion has been observed on lowering urinary pH [43]. Indeed, urinary pH was found to affect the renal excretion of methadone (clearance) but also its volume of distribution [43].…”

“…Earlier studies have indicated that an increase in methadone excretion has been observed on lowering urinary pH [43]. Indeed, urinary pH was found to affect the renal excretion of methadone (clearance) but also its volume of distribution [43]. Urinary pH modulates renal excretion of a number of drugs by the mechanism of nonionic diffusion as described by Milne et al [45].…”

The pharmacokinetics of methadone in healthy subjects and opiate users

“…A study in opiate-tolerant rats [41] has shown that enforced abstinence is associated with an increase in a 1 -acid glycoprotein, a major binding site for methadone in plasma [39]. Furthermore, opiate users about to begin a programme of methadone treatment are reported to have elevated plasma concentrations of this protein (1.22±0.10 s.d.…”

Therapeutic Drug Monitoring for Methadone: Scanning the Horizon

“…The picture in urine is often complex; unchanged methadone in urine only represents 2-5% of the total dose, the rest being excreted as metabolites. Furthermore, methadone excretion into urine is pH dependent so that, when urine is acidified for example, the amount of unchanged drug detected in urine is significantly increased [35]. Clinical interpretation is thus affected by inter-and intra-individual variation in values for urinary pH.…”