Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Abstract 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‐ 11 C] d ‐ threo ‐MP and [methyl‐ 11 C] 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 [ 11 C] l ‐ threo ‐MP than for oral [ 11 C] d ‐ threo ‐MP. Analysis of the chemical form of radioactivity in rat brain after [ 11 C] d ‐ threo ‐MP indicated mainly unchanged tracer, whereas with [ 11 C] l ‐ threo ‐MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [ 11 C]methanol or [ 11 C]CO 2 , 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.