The disposition of methoxyphenamine (o-methoxy-N,alpha-dimethylphenethylamine) and three of its metabolites was studied in five healthy volunteers on three occasions, with the urine pH separately under uncontrolled, acidic, and basic conditions. All five volunteers were extensive metabolizers of debrisoquine and methoxyphenamine, the latter with respect to O-demethylation and aromatic 5-hydroxylation. The plasma peak concentration and the area under the curve of methoxyphenamine from 0 to infinity did not differ significantly during the three phases of the study. However, on the average, its renal clearance increased by fivefold and its plasma terminal half-life decreased by twofold in the acidic as compared with the alkaline urine condition. The urinary excretions of methoxyphenamine and its metabolites N-desmethylmethoxyphenamine and O-desmethylmethoxyphenamine were significantly enhanced in the uncontrolled pH and the acidic urine conditions as compared with the alkaline urine condition. By contrast, the urinary excretion of the 5-hydroxymethoxyphenamine metabolite was not significantly affected by urinary pH variations. The mean urinary excretion ratios methoxyphenamine: O-desmethylmethoxyphenamine and N-desmethylmethoxyphenamine: O-desmethylmethoxyphenamine did not differ significantly during the three phases of the study, whereas the methoxyphenamine:5-hydroxymethoxyphenamine and N-desmethylmethoxyphenamine:5-hydroxymethoxyphenamine ratios were significantly altered during the alkaline phase as compared with the other two phases. Therefore, the ratios in terms of O-desmethylmethoxyphenamine are recommended for phenotyping individuals when using methoxyphenamine as a metabolic probe.