Brian kinetics of methylphenidate (Ritalin) enantiomers after oral adminstration

Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA.
Synapse (Impact Factor: 2.13). 09/2004; 53(3):168-75. DOI: 10.1002/syn.20046
Source: PubMed


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.

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    • "It was later recognised that the erythro form of MPH was responsible for the cardiovascular side effects of MPH, and thus MPH has been manufactured as an equal mixture of D and L-threo MPH. Studies have revealed that the D form is the primary active form of MPH (Ding et al., 1997[31], 2004[32]). Thus the D form is now available as tablets of 2.5, 5 and 10 mg. It is worth mentioning that 5 mg D-MPH is equivalent to 10 mg MPH-IR. "
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    • "Previous studies examining the pharmacokinetics of methylphenidate in rodent models also showed that brain concentrations of the compound were consistently higher than plasma concentrations (Patrick et al., 1984; Thai et al., 1999) and that similar to our results, maximal plasma and brain concentrations of D-methylphenidate were attained within 10 min of administration (Thai et al., 1999). A positron emission tomography study using orally administered radiolabeled D-and L-methylphenidate also found higher levels of Lmethylphenidate in the brains of baboons and rats (Ding et al., 2004). Our finding of 4-8 fold difference between brain and plasma concentration of D-methylphenidate at 15 and 30 min following 0.75mg/kg methylphenidate administration tend to agree with findings from earlier studies using intraperitoneal (37μM/kg) or oral (1 mg/kg) administration (Kotaki et al., 1988; Patrick et al., 1984; Thai et al., 1999). "
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    • "First, most animal studies using methylphenidate use an i.p. application rather than an oral treatment. Due to differences in the bioavailability of i.p. and orally administered methylphenidate (Ding et al., 2004; Faraj et al., 1974) it is assumed that methylphenidate exerts different effects on the dopaminergic system depending on the method of application. The dose used for oral methylphenidate application in our study was based on the faster hepatic drug metabolism of the gerbil and reflects a clinically relevant dose comparable to the therapeutical dose used in children with ADHD (Grund et al., 2007; cf. "
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