Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate (MPH) and its major metabolite, dl-ritalinic acid (RA), were examined in a cohort of healthy subjects. On two occasions, separated by one week, each subject received MPH.HCl either intravenously (10 mg) or orally (40 mg). Urine was collected in six time segments, up to 16 h after each dosing. In the first 2 h after oral administration of MPH, d-MPH found in the urine was 10-fold greater than the l-antipode, whereas there was no significant difference between the amounts of MPH enantiomers excreted after the intravenous dose. Examination of RA content in the 0-2-h urine samples after oral administration of MPH indicated the presence of higher levels of l-RA (d-RA:l-RA, 0.37), whereas after intravenous MPH, there was no significant difference between the amounts of RA enantiomers. Moreover, after oral administration of MPH, the ratio of d-MPH to l-MPH was approximately 10 in urine samples from each of the time segments. By contrast, after intravenous administration of MPH, the d:l ratio changed progressively from 1.16 in the 0-2-h urine sample to 9.06 in the 12-16-h sample. These observations suggest that, after oral administration of dl-MPH, the distortion in the ratio of MPH or RA enantiomers in urine samples was attributable to enantioselective presystemic conversion of MPH to RA rather than to enantioselective excretion.