Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers

Abstract

We have studied the pharmacokinetics of methylphenidate enantiomers after the oral administration of different doses of racemic methylphenidate to one patient with narcolepsy and to four healthy volunteers. The plasma concentrations of (+)-methylphenidate were much higher than those of (-)-methylphenidate after each dose in all subjects. In the patient the oral clearance (CL/f) of (+)-methylphenidate fell 3-fold and the area under the concentration-time curve (AUC) rose 7-fold when the dose was increased from 20 to 40 mg (from 0.27 to 0.53 mg.kg-1), in spite of the relatively constant terminal half-life of 2.6-2.7 h. Similar dose-dependency was also observed in the healthy volunteers in the dose range of 10-60 mg (0.12-0.77 mg.kg-1). The mean value of CL/f for the 40 mg dose was significantly lower than that for the 20 mg dose. The mean AUC of the (+)-isomer corrected to a dose of 10 mg increased significantly between the 20 mg and 40 mg doses. In the urine (+)- and (-)-ritalinic acid were excreted for 48 h after each dose as 32-37% and 34-40% of the dose respectively. The mean total recoveries (sum of enantiomers of methylphenidate and its metabolite, ritalinic acid) in the urine were relatively constant (63-78% of the doses), suggesting that the changes in AUC with dose may not be due to a change in the intestinal absorption of racemic methylphenidate. We conclude that the nonlinear kinetics of (+)-methylphenidate may be due to saturation of its presystemic elimination.

Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects

“…The in vivo regional distribution in rat brain of the positive and negative enantiomers of DL-threomethylphenidate was investigated by Aoyama et al (1994a). Results obtained on administration of the individual enantiomers were similar to those obtained after administration of the racemate.…”

“…They also found some evidence that there may be dose dependency associated with the metabolism of racemicmethylphenidate. Aoyama et al (1993) reported that the positive enantiomer of methylphenidate showed dose-dependent kinetics in humans, probably because of saturation of the presystemic elimination of the drug.…”

The Single-Dose Pharmacokinetics of NWP06, a Novel Extended-Release Methylphenidate Oral Suspension

“…25 The ratio of d-MPH to l-MPH reported in other studies has varied considerably (5-to 230-fold). 16,25 In this study, the ratio of d-MPH to l-MPH for NWP06 and IR MPH easily falls within the range reported in the literature.…”

Differential Pharmacokinetics and Pharmacodynamics of Methylphenidate Enantiomers

“…This finding is consistent with that of extensive enantiospecific pharmacokinetic studies that have measured both isomers and found the l-isomer to generally attain only a small fraction of that of circulating concentrations of d-MPH (Table 1). [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] In addition, the plasma half-life (t 1/2 ) of d-MPH is markedly longer than that of l-MPH. 22 The presystemic metabolism and clearance of d,l-MPH is an enantioselective process resulting in markedly higher plasma concentrations of d-MPH relative to l-MPH.…”