Abstract

Threo-dl-methylphenidate-¹⁴C·HCl (MEPH-¹⁴C·HCl) was found to be extensively metabolized in man, dog, rat and mouse. Pronounced species differences in the metabolism of the drug were found. In human subjects, plasma levels of MEPH-¹⁴C were found always to be much higher after i.v. than after oral administration. After oral administration, 50 and 90% of the ¹⁴C was excreted in urine in 8 and 48 hours, respectively. This suggests essentially complete absorption of MEPH. The main urinary metabolite was the deesterified product, ritalinic acid (RA), accounting for 80% of the dose. Upon i.v. administration of MEPH-¹⁴C·HCl to dogs, 50 to 60% of the radioactivity was excreted in 7-hour urine. The major metabolites in dog urine were RA and threo-dl-2-phenyl-2-(2'-piperidyl-6'-one) acetic acid (oxo-RA). In rats, both after i.p. and oral administration of MEPH-¹⁴C·HCl, 50 to 60% of the ¹⁴C was eliminated in urine and 30 to 40% in feces within 48 hours. Significant biliary excretion of ¹⁴C (25-30% in 12 hours) was found in bile-cannulated rats. The major metabolites in rat urine besides RA were threo-dl-2-(p-hydroxyphenyl)-2-(2'-piperidyl) acetic acid (p-OH RA), its methyl ester (p-OH MEPH)and the glucuronide conjugate of p-OH RA. The locomotor activity of MEPH, certain metabolites and N-acetyl MEPH was studied in mice.