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Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d‐ and l‐threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d‐isomer. A recent report that intraperitoneally (i.p.) administered l‐threo‐MP displayed potent, dose‐dependent inhibition of cocaine‐ or apomorphine‐induced locomotion in rats, raises the question of whether l‐threo‐MP has a similar effect when given orally. It has been speculated that l‐threo‐MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l‐threo‐MP or its metabolites can be delivered to the brain when it is given orally, and whether l‐threo‐MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C‐11‐labeled d‐ and l‐threo‐MP ([methyl‐11C]d‐threo‐MP and [methyl‐11C]l‐threo‐MP). In addition, we assessed the effects of i.p. l‐threo‐MP on spontaneous and cocaine‐stimulated locomotor activity in mice. There was a higher global uptake of carbon‐11 in both baboon and rat brain for oral [11C]l‐threo‐MP than for oral [11C]d‐threo‐MP. Analysis of the chemical form of radioactivity in rat brain after [11C]d‐threo‐MP indicated mainly unchanged tracer, whereas with [11C]l‐threo‐MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [11C]methanol or [11C]CO2, derived from demethylation, was excluded by ex vivo studies in rats. When l‐threo‐MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l‐threo‐MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l‐threo‐MP may not be pharmacologically active. These results are pertinent to the question of whether l‐threo‐MP contributes to the behavioral and side effect profile of MP during treatment of ADHD. Synapse 53:168–175, 2004. © 2004 Wiley‐Liss, Inc.