Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?

d,l-threo-methylphenidate (MPH) is an effective first-line treatment for the symptoms associated with attention-deficit/hyperactivity disorder. threo-methylphenidate inhibits the dopamine transporter and the norepinephrine transporter, resulting in elevations of these monoamines after impulse release. Although MPH has long been administered as a racemic mixture of the 2 enantiomers, d-MPH and l-MPH, converging lines of evidence drawn from investigations using in vitro systems, animal models, and humans indicate that it is predominantly, if not exclusively, d-MPH that mediates the pharmacological/therapeutic actions of MPH. In both rodent and primate animal models, the binding of radiolabeled d-MPH to dopamine transporter was found to be selective, saturable, and reversible, whereas binding of l-MPH was diffuse and nonspecific. The behavioral effects of the enantiomers of MPH have been tested in several animal models, and results indicate these observed behavioral changes are likewise mediated by d-MPH, whereas l-MPH has little or no effect.The contribution of the l-isomer to the overall pharmacological profile of the racemate remains unclear, owing to several studies suggesting that l-MPH may not be merely an inert isomeric ballast. For example, behavioral studies conducted in rats demonstrate an attenuation of the effect of d-MPH in animals pretreated with l-MPH, suggesting that l-MPH may interfere with the action of the active enantiomer. The importance of MPH chirality to central nervous system MPH receptor targeting has culminated in human imaging studies revealing that d-MPH binds specifically to striatal structures, whereas l-MPH binding is nonspecific. Taken together, data from in vitro, animal, and human studies support the premise that the d-enantiomer of MPH mediates the neurophysiological actions of MPH and therefore likely mediates its clinical efficacy.