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-(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.
Ding
Yu-Shin
YS
Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA. ding@bnl.gov
Gatley
S John
SJ
Thanos
Panayotis K
PK
Shea
Colleen
C
Garza
Victor
V
Xu
Youwen
Y
Carter
Pauline
P
King
Payton
P
Warner
Don
D
Taintor
Nicholas B
NB
Park
Daniel J
DJ
Pyatt
Bea
B
Fowler
Joanna S
JS
Volkow
Nora D
ND
D000284:Administration, Oral; D000327:Adsorption / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D007536:Isomerism; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010215:Papio; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate; D003042:Cocaine