Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

  title={Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration},
  author={Yu-Shin Ding and S. John Gatley and Panayotis K. Thanos and Colleen Shea and Victor Garza and Youwen Xu and Pauline Carter and Payton King and Donald Warner and Nicholas B Taintor and Daniel J. Park and Beatrice Pyatt and Joanna S. Fowler and Nora D. Volkow},
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… 

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

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.

New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder

The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics.

A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study.

The emerging data of favorable therapeutic effects of ADHD treatment with d-MPH may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior.

Pharmacokinetics, dose‐range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice

Results indicated that although MPH induced liver hypertrophy in mice, no genotoxicity was observed and the reactive metabolite, ritalinic acid (RA), was evaluated.

Short- and Long-Term Stability of Methylphenidate and its Metabolites in Blood.

It was concluded that d,l-methylphenidate breaks down in the blood to its metabolite ritalinic acid and may make data interpretation difficult if samples are not properly stored and the optimal storage for these analytes is recommended at -20°C.

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior

Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder

This paper reviews and summarizes the available research literature on d-MPH regarding pharmacodynamic, pharmacokinetic, chemical structure, receptor binding, toxicology, and clinical perspectives and potentially may offer some advantages in the realms of absorption and duration of action compared with its racemic counterpart.

Methylphenidate HCl: therapy for attention deficit hyperactivity disorder

Analysis of the National Institutes of Health-sponsored multimodal treatment study of attention deficit hyperactivity disorder supports a combined medication and behavioral therapy approach.



Enantioselective pharmacokinetics and pharmacodynamics of dl‐thero‐mcthylphenidate in children with attention deficit hyperactivity disorder

The computer tests revealed a drug‐induced improvement in sustained attention that was entirely attributable to the d‐enantiomer, and there was no evidence to suggest that the effectiveness of d‐methylphenidate was in any way compromised by the presence of its antipode.

Comparison between intraperitoneal and oral methylphenidate administration: A microdialysis and locomotor activity study.

It is shown that relatively low doses of MP significantly increase extracellular DA and locomotor activity and indicates that the differences in the neurochemical and behavioral effects of MP between the intragastric and the i.p. routes are due to central drug bioavailability.

Pharmacokinetics and in vivo specificity of [LLC]dl‐threo‐methylphenidate for the presynaptic dopaminergic neuron

The results demonstrate the saturable [11C]MP binding to the dopamine transporter in the baboon brain and that [11 C]MP is sensitive to dopamine neuron degeneration in Parkinson's disease.

Distribution of methylphenidate and p-hydroxymethylphenidate in rats.

The data suggest that the central effects of MPH do not depend upon conversion to HOMPH, and that the main action of MPH is determined by itself and not by the metabolite threo-dl-p-hydroxymethylphenidate.

Enantioselective Pharmacokinetics of dl-threo-Methylphenidate in Humans

It was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans.

Observations suggest that, after oral administration of dl-MPH, the distortion in the ratio of MPH or RA enantiomers in urine samples was attributable to enantioselective presystemic conversion of MPH to RA rather than to en Anti-inflammatory excretion.

Evidence that dogs do not model enantioselective pharmacokinetics of dl-methylphenidate in humans.

Abstract To the Editor: Attention-deficit hyperactivity disorder (ADHD) in children is characterized by varying degrees of inattention, impulsiveness, and hyperactivity. Many children with ADHD

Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the human and baboon brain

Results indicate that pharmacological specificity of MP resides entirely in the d-threo isomer and directly show that binding of the l-isomer in human brain is mostly non-specific.

Pharmacology of the enantiomers of threo-methylphenidate.

Results suggest that synaptic inhibition of catecholaminergic uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.

Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit-hyperactivity disorder.

The purpose of this present investigation was to determine whether the levels of methylphenidate were sustained for over a time period of 8 h, and to examine enantioselective aspects of the pharmacokinetics following the ingestion of the sustained-release formulation.